Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors

ABSTRACT

The invention relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula:where m, n, X1, X2, R1-R5, R5′ and R6 are described herein.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/098,141, filed Dec. 30, 2014, the entire contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention is directed to inhibitors of ubiquitin-specificprotease 7 (USP7) useful in the treatment of diseases or disordersassociated with USP7 enzymes. Specifically, the invention is concernedwith compounds and compositions inhibiting USP7, methods of treatingdiseases or disorders associated with USP7, and methods of synthesis ofthese compounds.

BACKGROUND OF THE INVENTION

Ubiquitination is a post translational modification initially identifiedas a crucial component of proteasomal degradation in the ubiquitinproteasome system (UPS). Chains of Ubiquitin (Ub(s)), an 8.5 kDa highlyconserved protein, are covalently attached to substrates to be degradedin the proteasome (Finley D. “Recognition and processing ofubiquitin-protein conjugates by the proteasome.” Annual review ofbiochemistry 78:477-513, (2009)) The molecular mechanisms by which theUPS acts are also varied, with different chain linkages ofubiquitination controlling protein turnover, enzymatic activity,subcellular localization, and protein-protein interactions of substrateproteins. (Komander D., et. al. “The emerging complexity of proteinubiquitination,” Biochem. Soc. Trans. 37(Pt 5):937-53 (2009))

Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific Protease(USP) family deubiquitinase (DUB) that was originally identified as anenzyme that interacted with virally-encoded proteins of the Herpessimplex virus and later the Epstein-Barr virus (Everett R. D., MeredithM., Orr A., Cross A, Kathoria M., Parkinson J. “A novelubiquitin-specific protease is dynamically associated with the PMLnuclear domain and binds to a herpes virus regulatory protein,” EMBO J.16(7):1519-30 (1997); Holowaty M. N., Zeghouf M., Wu H., et al. “Proteinprofiling with Epstein-Barr nuclear antigen-1 reveals an interactionwith the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7,”J. Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases(USPs) specifically cleave the isopeptide bond at the carboxy terminusof ubiquitin. In contrast to other DUB classes, which are thought togenerally regulate ubiquitin homeostasis or to be involved inpre-processing of linear ubiquitin chains, USPs remove ubiquitin fromspecific targets. Given this substrate specificity combined with thenumerous roles ubiquitination has in the cell, USPs are importantregulators of a multitude of pathways, ranging from preventing theproteolysis of ubiquitinated substrates, to controlling their nuclearlocalization.

USP7 deubiquitinates a variety of cellular targets involved in differentprocesses related to cancer and metastasis, neurodegenerative diseases,immunological disorders, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, and bacterial infections and diseases.

For example, USP7 has been shown to stabilize DNMT1, a DNAmethyltransferase that maintain epigenetic silencing, to maintain highersteady state-levels of Claspin, a protein involved in ataxiatelangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and toregulate Tip60 protein levels, a histone acetyltransferase andtranscriptional coregulator involved in adipogenesis. (Zhanwen du, SongJ., Wang Y., et al. “DNMT1 stability is regulated by proteinscoordinating deubiquitination and acetylation-driven ubiquitination,”Science Signaling 3(146) (2010); Faustrup H., Bekker-Jensen S., BartekJ., Lukas J., Mail N., Mailand N. “USP7 counteracts SCFbetaTrCP—but notAPCCdh1-mediated proteolysis of Claspin,” The Journal of cell biology184(1):13-9 (2009); Gao Y., Koppen A., Rakhsh M., et al. “Earlyadipogenesis is regulated through USP7-mediated deubiquitination of thehistone acetyltransferase TIP60,” Nature Communications 4:2656 (2013)

In addition to regulating the protein stability of poly-ubiquitinatedtargets, USP7 also acts to control the subcellular localization ofproteins. Mono-ubiquitination of PTEN has been shown to effect itscytoplasmic/nuclear partitioning, where nuclear localization of PTEN isimportant for its tumor suppression activity. (Trotman L. C., Wang X.,Alimonti A., et al. “Ubiquitination regulates PTEN nuclear import andtumor suppression,” Cell 128(1):141-56 (2007); Song M. S., Salmena L.,Carracedo A., et al. “The deubiquitinylation and localization of PTENare regulated by a HAUSP-PML network,” Nature 455(7214):813-7 (2008))USP7 has also been shown to bind and deubiquitinate FOXO4, a member ofthe FOXO subfamily of transcription factors involved in a variety ofcell processes including metabolism, cell cycle regulation apoptosis,and response to oxidative stress, decreasing its nuclear localizationand transcriptional activity. (van der Horst A., van der Horst O., deVries-Smits A. M. M., et al. “FOXO4 transcriptional activity isregulated by monoubiquitination and USP7/HAUSP,” Nat. Cell Biol.8(10):1064-73 (2006))

Cellular targets of USP7 also include the tumor suppressor p53 and itsmajor E3 ligase, MDM2, stabilizing p53 via the degradation of MDM2. (LiM., Chen D., Shiloh A., et al. “Deubiquitination of p53 by HAUSP is animportant pathway for p53 stabilization,” Nature 416(6881):648-53(2002); Li M., Brooks C. L., Kon N., Gu W. “A dynamic role of HAUSP inthe p53-Mdm2 pathway,” Mol. Cell. 13(6):879-86 (2004)) Structuralstudies have also shown that the EBNA1 protein encoded by theEpstein-Barr virus interacts at the same binding surface as USP7 on p53,preventing USP7 endogenous cellular activity while recruiting USP7 toviral promoters in order to activate latent viral gene expression.(Saridakis V., et al. “Structure of the p53 binding domain of HAUSP/USP7bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediatedimmortalization,” Mol. Cell. 18(1):25-36 (2005); Sarkari F.,Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y., Frappier L.“EBNA1-mediated recruitment of a histone H2B deubiquitylating complex tothe Epstein-Barr virus latent origin of DNA replication,” PLoS pathogens5(10) (2009); Sheng Y., et al. “Molecular recognition of p53 and MDM2 byUSP7/HAUSP,” Nat. Struct. Mol. Biol. 13(3):285-91 (2006)) Similarly, thegene product of TSPYL5, a gene frequently amplified in breast cancer andassociated with poor clinical outcome, alters the ubiquitination statusof p53 via its interaction with USP7. (Epping M. T., et al. “TSPYL5suppresses p53 levels and function by physical interaction with USP7,”Nat. Cell Biol. 13(1):102-8 (2011))

Inhibition of USP7 with small molecule inhibitors therefore has thepotential to be a treatment for cancers and other disorders. For thisreason, there remains a considerable need for novel and potent smallmolecule inhibitors of USP7.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

X₂ is CR₇ or N;

R₁ is H, D, —OH, —SH, —NH₂, —NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F;R₂ is (C₂-C₆) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —CN, —OH, —C(O)R₁₇, —C(O)OR₁₇, —OC(O)OR₁₇, —OC(O)NR₁₇R₁₈,—NR₁₇R₁₈, —NR₁₇C(O)R₁₈, —NR₁₇C(O)OR₁₈, —C(O)NR₁₇R₁₈, —NR₁₇C(O)NR₁₇R₁₈,—S(O)_(q)NR₁₇R₁₈, —S(O)_(q)R₁₇R₁₈, —NR₁₇S(O)_(q)R₁₇R₁₈, or halogen,wherein alkyl is optionally substituted with one or more substituentsindependently selected from —OH or —NH₂;

or two R₃ together when on adjacent carbons form a (C₃-C₈) cycloalkyloptionally substituted with one or more R₁₉; or two R₃ together form a(C₃-C₈) spirocycloalkyl optionally substituted with one or more R₁₉; ortwo R₃ together form a spiroheterocyclyl optionally substituted with oneor more R₁₉; or two R₃ together when on adjacent carbons form an arylring optionally substituted with one or more R₁₉, or two R₃ togetherwhen on adjacent carbons form an heteroaryl ring optionally substitutedwith one or more R₁₉;

R₄ is (C₁-C₆) alkyl, —(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈)cycloalkyl, CD₃ or heterocyclyl, wherein aryl, heteroaryl, heterocyclyland cycloalkyl are optionally substituted with one or more R₁₂;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,or halogen; or

R₅ and R_(5′) together form a (C₃-C₆) cycloalkyl or heterocyclyl ringoptionally substituted with one or more substituents independentlyselected from halogen, —CN, (C₁-C₆) alkyl, —OH, —CH₂OH,—(C₀-C₂)-alkylene-O(C₁-C₆) alkyl, or —(C₀-C₂)-alkylene-NR₁₇R₁₈;

R₆ is independently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH when X₂ is N;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, aryl,heteroaryl, —CN, or —NR₁₀R₁₁, wherein aryl and heteroaryl is optionallysubstituted with one or more R₁₀;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, heterocyclyl, andcycloalkyl are optionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅, —S(O)NR₁₄R₁₅,—NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, andheteroaryl are substituted with one or more substituents independentlyselected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅, —OH, —CN, —C(O)R₁₄, or—NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

each R₁₇ and R₁₈ is at each occurrence independently H or (C₁-C₆) alkyl;

R₁₉ is independently at each occurrence H, D, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, halogen, —CN, or —NR₁₇R₁₈;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibitingUSP7. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating aneurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a viralinfection or disease. The method comprises administering to a patient inneed thereof an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating aninflammatory disease or condition. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells and/or enhanced tumor-specificT-cell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the present invention relates to a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for treating a disease associated with inhibiting USP7.

Another aspect of the present invention relates to the use of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, in the treatment of adisease associated with inhibiting USP7.

The present invention further provides methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present invention provides inhibitors of USP7 that are therapeuticagents in the treatment of diseases such as cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present invention further provides compounds and compositions withan improved efficacy and safety profile relative to known USP7inhibitors. The present disclosure also provides agents with novelmechanisms of action toward USP7 enzymes in the treatment of varioustypes of diseases including cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases. Ultimately thepresent invention provides the medical community with a novelpharmacological strategy for the treatment of diseases and disordersassociated with USP7 enzymes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that arecapable of inhibiting the activity USP7. The invention features methodsof treating, preventing or ameliorating a disease or disorder in whichUSP7 plays a role by administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present inventioncan be used in the treatment of a variety of USP7 dependent diseases anddisorders by inhibiting the activity of USP7 enzymes. Inhibition of USP7provides a novel approach to the treatment, prevention, or ameliorationof diseases including, but not limited to, cancer and metastasis,neurodegenerative diseases, immunological disorders, osteoporosis,arthritis inflammatory disorders, cardiovascular diseases, ischemicdiseases, viral infections and diseases, and bacterial infections anddiseases.

In a first aspect of the invention, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein m, n, X₁, X₂, R₁-R₅,R_(5′) and R₆ are as described herein above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl), —N((C₁-C₆)alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl, —S(O)₂(C₁-C₆)alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂. The substituentscan themselves be optionally substituted. “Optionally substituted” asused herein also refers to substituted or unsubstituted whose meaning isdescribed below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, NH₂,NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,i.e., —O(alkyl). Examples of alkoxy groups include without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-24 carbon atoms further substituted with (C₁-C₆) alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingformula

where m is an integer from 1 to 6 and n is an integer from 1 to 16. Thecycloalkyl ring or carbocycle may be optionally substituted by one ormore substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.Examples of cycloalkyl groups include, without limitations, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl,decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl,cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl,1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl,3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl,bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl,2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbonand heteroatoms taken from oxygen, nitrogen, or sulfur and wherein thereis not delocalized n electrons (aromaticity) shared among the ringcarbon or heteroatoms. The heterocycloalkyl ring structure may besubstituted by one or more substituents. The substituents can themselvesbe optionally substituted. Examples of heterocyclyl rings include, butare not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, oxazolidinonyl, and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡N.

The term “amine” as used herein refers to primary (R—NH₂, R≠H),secondary (R₂—NH, R₂≠H) and tertiary (R₃—N, R≠H) amines. A substitutedamine is intended to mean an amine where at least one of the hydrogenatoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom. Specifically, NH₂, —NH(alkyl) or alkylamino,—N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamidesubstituents are included in the term “amino”.

The term “dialkylamino” as used herein refers to an amino or NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, i.e., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of alkylaminogroups include, but are not limited to, dimethylamino (i.e., —N(CH₃)₂),diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃-C₁₂)spirocycloalkyl is a spirocycle containing between 3 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present invention relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting USP7, which are useful for thetreatment of diseases and disorders associated with modulation of a USP7enzyme. The invention further relates to compounds, or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, which are useful for inhibiting USP7.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ta):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈; R₄ is (C₁-C₆) alkyl,—(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈) cycloalkyl, CD₃, orheterocyclyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl areoptionally substituted with one or more R₁₂;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, or halogen; or

R₆ is independently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(Q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

each R₁₇ and R₁₈ is independently at each occurrence H or (C₁-C₆) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ib):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

R₄ is (C₁-C₆) alkyl, —(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈)cycloalkyl, CD₃, or heterocyclyl, wherein aryl, heteroaryl, heterocyclyland cycloalkyl are optionally substituted with one or more R₁₂;

R₅ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, or halogen; or

R₆ is independently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH when X₂ is N;

R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, aryl,heteroaryl, —CN, or —NR₁₀R₁₁, wherein aryl and heteroaryl is optionallysubstituted with one or more R₁₀;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉, or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

each R₁₇ and R₁₈ is at each occurrence independently H or (C₁-C₆) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein.

X₁ is C, S, or S(O);

Y is CH or N;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₁; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R_(1S) are independently at each occurrence selected fromH, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2; and

r is 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Id):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

Y is CH or N;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2; and

r is 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

X₁ is C, S, or S(O);

R₁ is H, D, —OH, —SH, —NH₂, —NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,or halogen; or

R₅ and R_(5′) together form a (C₃-C₆) cycloalkyl or heterocyclyl ringoptionally substituted with one or more substituents independentlyselected from halogen, —CN, (C₁-C₆) alkyl, —OH, —CH₂OH,—(C₀-C₂)-alkylene-O(C₁-C₆) alkyl, or —(C₀-C₂)-alkylene-NR₁₇R₁₈;

R₆ is independently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH when X₂ is N;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R_(R) together when on adjacent carbons form an aryl ringoptionally substituted with one or more R₉; or two R₈ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₉; or two R_(R) together when on adjacent carbons form aheterocyclyl ring optionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

each R₁₇ and R₁₈ is at each occurrence independently H or (C₁-C₆) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein.

X₁ is C, S, or S(O);

R₁ is H, D, —OH, —SH, —NH₂, —NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R_(R);

R₅ and R_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,or halogen; or

R₅ and R_(5′) together form a (C₃-C₆) cycloalkyl or heterocyclyl ringoptionally substituted with one or more substituents independentlyselected from halogen, —CN, (C₁-C₆) alkyl, —OH, —CH₂OH,—(C₀-C₂)-alkylene-O(C₁-C₆) alkyl, or —(C₀-C₂)-alkylene-NR₁₇R₁₈;

R₆ is independently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH when X₂ is N;

each R_(R) is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R_(R) together when on adjacent carbons form an aryl ringoptionally substituted with one or more R₉; or two R₈ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₉; or two R₈ together when on adjacent carbons form aheterocyclyl ring optionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₁C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

each R₁₇ and R₁₈ is at each occurrence independently H or (C₁-C₆) alkyl;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

R₄ is (C₁-C₆) alkyl, —(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈)cycloalkyl, CD₃, or heterocyclyl, wherein aryl, heteroaryl, heterocyclyland cycloalkyl are optionally substituted with one or more R₁₂;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN; or R₁₀and R₁₁ together form a heterocyclyl ring optionally substituted withone or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

R₄ is (C₁-C₆) alkyl, —(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈)cycloalkyl, CD₃, or heterocyclyl, wherein aryl, heteroaryl, heterocyclyland cycloalkyl are optionally substituted with one or more R₁₂;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2; and

each q is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

Y is CH or N;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈;

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁OR₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2 and

r is 0, 1, 2, 3, 4, or 5.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ij):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof,

wherein:

Y is CH or N;

R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R_(R);

each R₈ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH, wherein alkyl, alkylene, aryl, heteroaryl, and heterocyclyl areoptionally substituted with one or more R₉;

or two R₈ together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₉; or two R₈ together when on adjacentcarbons form a heteroaryl ring optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₉;

each R₉ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN,—C(O)R₁₀, —C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, —O-aryl, CN, or —O-heteroaryl, wherein alkyl,aryl, and cycloalkyl are optionally substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, halogen, aryl, —NR₁₄C(O)R₁₅, —NR₄S(O)_(q)R₁₅, —OH or—CN;

or two R₉ together when on adjacent carbons form an aryl ring; or two R₉together when on adjacent carbons form a heteroaryl ring; or two R₉together when on adjacent carbons form a (C₃-C₁₀) cycloalkyl ring;

each R₁₀ and R₁₁ is independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl,—(C₀-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl,—(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN;

or R₁₀ and R₁₁ together form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅;

each R₁₂ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl, aryl,heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₃;

each R₁₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy,(C₁-C₆) hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅;

or two R₁₃ together when on adjacent carbons form a heterocyclyl ringoptionally substituted with one or more R₁₆; or two R₁₃ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₁₆; or two R₁₃ together with the carbon to which they areattached can form a spiroheterocyclyl optionally substituted with one ormore R₁₆;

each R₁₄ and R₁₅ are independently at each occurrence selected from H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-aryl, —(C₀-C₄) alkylene-heteroaryl, or —CN, wherein alkyl,alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R₁₆;

or R₁₄ and R₁₅ together form a heterocyclyl ring optionally substitutedwith one or more R₁₆;

each R₁₆, is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl,—CN, —CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH;

or two R₁₆ together when on adjacent carbons form an aryl ring; or twoR₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;

p is 0, 1, or 2;

each q is 0, 1, or 2 and

r is 0, 1, 2, 3, 4, or 5.

In some embodiments of the Formulae above, X₁ is C, S, or S(O). Inanother embodiment, X₁ is C. In yet another embodiment, X₁ is S. Inanother embodiment, X₁ is S(O).

In some embodiments of the Formulae above, X₂ is N. In anotherembodiment, X₂ is CR₇.

In some embodiments of the Formulae above, R₁ is H, D, —OH, —SH, —NH₂,—NH(C₁-C₄) alkyl, —N((C₁-C₄) alkyl)₂, or F. In another embodiment, R₁ is—OH, —SH, —NH₂, —NH(C₁-C₂) alkyl, —N((C₁-C₂) alkyl)₂, or F. In yetanother embodiment, R₁ is —OH, —SH, —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂ or F. In another embodiment, R₁ is —OH, —NH₂, —NHCH₃,—N(CH₃)₂, or F. In yet another embodiment, R₁ is —OH, —NH₂, or F.

In some embodiments of the Formulae above embodiment, R₂ is (C₁-C₈)alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, orOR₁₀. In this embodiment, alkyl, aryl, cycloalkyl, and heterocyclyl areoptionally substituted with one or more R₈.

In some embodiments of the Formulae above, R₃ is D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—CN, —OH, —C(O)R₁₇, C(O)OR₁₇, —OC(O)OR₁₇, —OC(O)NR₁₇R₁₈, —NR₁₇R₁₈,—NR₁₇C(O)R₁₈, —NR₁₇C(O)OR₁₈, —C(O)NR₁₇R₁₈, —NR₁₇C(O)NR₁₇R₁₈,—S(O)_(q)NR₁₇R₁₈, —S(O)_(q)R₁₇R₁₈, —NR₁₇S(O)_(q)R₁₇R₁₈, or halogen. Inanother embodiment, R₃ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, or —OH In yetanother embodiment, R₃ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, or —OH. In yet anotherembodiment, R₃ is selected from (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, or —OH In another embodiment, R₃ isselected from (C₁-C₃) alkyl, (C₁-C₃) alkoxy, or —OH. In anotherembodiment, R₃ is selected from methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, isopropoxy, or —OH.

In some embodiments of the Formulae above, two R₃ together when onadjacent carbons can form a (C₃-C₈) cycloalkyl optionally substitutedwith one or more R₁₉. In another embodiment, two R₃ together when onadjacent carbons can form a (C₃-C₈) spirocycloalkyl optionallysubstituted with one or more R₁₉. In another embodiment, two R₃ togetherwhen on adjacent carbons can form a spiroheterocyclyl optionallysubstituted with one or more R₁₉. In yet another embodiment, two R₃together when on adjacent carbons can form an aryl ring optionallysubstituted with one or more R₁₉. In another embodiment, two R₃ togetherwhen on adjacent carbons can form a heteroaryl ring optionallysubstituted with one or more R₁₉.

In some embodiments of the Formulae above, R₄ is (C₁-C₆) alkyl, —(C₀-C₃)alkylene-aryl, heteroaryl, (C₃-C₈) cycloalkyl, CD₃, or heterocyclyl,where the aryl, heteroaryl, heterocyclyl and cycloalkyl are optionallysubstituted with one or more R₁₂.

In some embodiments of the Formulae above, R₅ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, or halogen. In another embodiment, R₅ is H, D,(C₁-C₃) alkyl, (C₂-C₃) alkenyl, (C₂-C₃) alkynyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, or halogen. In yet another embodiment, R₅is H, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, or halogen. Inanother embodiment, R₅ is H or (C₁-C₃) alkyl. In yet another embodiment,R₅ is H, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R₅ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, or halogen. In another embodiment, R_(5′) is H, D,(C₁-C₃) alkyl, (C₂-C₃) alkenyl, (C₂-C₃) alkynyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, or halogen. In yet another embodiment,R₅, is H, D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, orhalogen. In another embodiment, R₅ is H or (C₁-C₃) alkyl. In yet anotherembodiment, R_(5′) is H, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R₅ and R_(5′) together canform a (C₃-C₆) cycloalkyl or heterocyclyl ring optionally substituted.The optional substituents can be halogen, —CN, (C₁-C₆) alkyl, —OH,—CH₂OH, —(C₀-C₂)-alkylene-O(C₁-C₆) alkyl, or —(C₀-C₂)-alkylene-NR₁₇R₁₈.

In some embodiments of the Formulae above, R₆ is H, D, halogen, —CN,—NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, or —OH. In another embodiment,R₆ is H, D, halogen, —CN, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, or —OH. In yetanother embodiment, R₆ is H, halogen, or (C₁-C₃) alkyl In anotherembodiment, R₆ is H, F, Cl, methyl, ethyl, propyl, or isopropyl.

In some embodiments of the Formulae above, R₇ is H, D, (C₁-C₆) alkyl,(C₁-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, or —NR₁₀R₁₁. In another embodiment, R₇ isH, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, or halogen. In yet anotherembodiment, R₇ is H, D, (C₁-C₃) alkyl, (C₂-C₃) alkenyl, (C₂-C₃) alkynyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkoxy, or halogen. Inanother embodiment, R₇ is H, D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkyl, (C₁-C₃) haloalkoxy, or halogen. In yet another embodiment, R₇is H, D, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkyl, or halogen.In another embodiment, R₇ is H, (C₁-C₃) alkyl, or halogen. In yetanother embodiment, R₇ is H, methyl, ethyl, propyl, isopropyl, F or Cl.In another embodiment, R₇ is H or methyl.

In some embodiments of the Formulae above, R₈ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,—(C₁-C₃)-alkylene-O(C₁-C₆) alkyl, —(C₀-C₄)-alkylene-aryl,—(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀) cycloalkyl, heterocyclyl,—(C₀-C₄)-alkylene-O-aryl, —(C₀-C₄)-alkylene-O-heteroaryl,—O—(C₃-C₈)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀,—C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁,—(C₀-C₃)-alkylene-NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁,—NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅, or—OH. In this embodiment, alkyl, alkylene, aryl, heteroaryl, andheterocyclyl can be optionally substituted with one or more R₉.

In some embodiments of the Formulae above, two R₈ together when onadjacent carbons can form an aryl ring optionally substituted with oneor more R₉. In yet another embodiment, two R_(a) together when onadjacent carbons can form a heteroaryl ring optionally substituted withone or more R₉. In another embodiment, two R₈ together when on adjacentcarbons can form a heterocyclyl ring optionally substituted with one ormore R₉.

In some embodiments of the Formulae above, R₉ is D, (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R₁₀,—C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁,—NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅,—O-aryl, or —O-heteroaryl. The alkyl, aryl, and cycloalkyl areoptionally substituted with one or more substituents independentlyselected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, halogen,aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or —CN.

In some embodiments of the Formulae above, two R₉ together when onadjacent carbons can form an aryl ring. In another embodiment, two R₉together when on adjacent carbons can form a heteroaryl ring. In anotherembodiment, two R₉ together when on adjacent carbons can form a (C₃-C₁₀)cycloalkyl ring.

In some embodiments of the Formulae above, R₁₀ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl, —(C₀-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-heteroaryl, or —CN. The alkyl, alkenyl, alkynyl, alkylene,cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN.

In some embodiments of the Formulae above, R₁₁ is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl, —(C₀-C₄)alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-heteroaryl, or —CN. The alkyl, alkenyl, alkynyl, alkylene,cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₈) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN.

In some embodiments of the Formulae above, R₁₀ and R₁₁ together when onadjacent carbons can form a heterocyclyl ring optionally substitutedwith one or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅.

In some embodiments of the Formulae above, R₁₂ is selected from D,(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₈) cycloalkyl,aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₈)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, and cycloalkyl areoptionally substituted with one or more R₁₃.

In one embodiment, R₁₃ is selected from D, (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)R₁₄, —NR₁₄S(O)_(q)R₁₅, —S(O)_(q)NR₁₄R₁₅,—NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl, andheteroaryl are substituted with one or more substituents independentlyselected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅, —OH, —CN, —C(O)R₁₄, or—NR₁₄R₁₅

In another embodiment, two R₁₃ together when on adjacent carbons form aheterocyclyl ring optionally substituted with one or more R₁₆. In yetanother embodiment, two R₁₃ together when on adjacent carbons form aheteroaryl ring optionally substituted with one or more R₁₆. In anotherembodiment, two R₁₃ together with the carbon to which they are attachedcan form a spiroheterocyclyl optionally substituted with one or moreR₁₆.

In one embodiment, R₁₄ is H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆)alkynyl, —(C₁-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄)alkylene-heterocyclyl, —(C₀-C₄) alkylene-aryl, —(C₀-C₄)alkylene-heteroaryl, or —CN, where the alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more R₁₆.

In some embodiments of the Formulae above, R_(1S) is H, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄) alkylene-(C₃-C₈) cycloalkyl,—(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄) alkylene-aryl, —(C₀-C₄)alkylene-heteroaryl, or —CN, where the alkyl, alkenyl, alkynyl,alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more R₁₆.

In some embodiments of the Formulae above, R₁₄ and R₁₅ together can forma heterocyclyl ring optionally substituted with one or more R₁₆.

In some embodiments of the Formulae above, R₁₆ is D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl, —CN,—CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH. In another embodiment, two R₁₆ together when on adjacent carbonscan form an aryl ring. In yet another embodiment, two R₁₆ together whenon adjacent carbons can form a spiroheterocyclyl ring.

In some embodiments of the Formulae above, R₁₇ is H or (C₁-C₆) alkyl. Inanother embodiment, R₁₇ is independently H or (C₁-C₄) alkyl. In yetanother embodiment, R₁₇ is independently H, methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, or tert-butyl.

In some embodiments of the Formulae above, R₁₈ is H or (C₁-C₆) alkyl. Inanother embodiment, R₁₈ is independently H, methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, or tert-butyl.

In some embodiments of the Formulae above, R₁₈ is H, D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, halogen, —CN, or —NR₁₇R₁₈.

In some embodiments of the Formulae above, m is 0, 1 or 2. In anotherembodiment, m is 0 or 1.

In some embodiments of the Formulae above, n is 0, 1, 2 or 3. In anotherembodiment, n is 0, 1, or 2. In another embodiment, n is 1.

In some embodiments of the Formulae above, p is 0. In anotherembodiment, p is 1. In yet another embodiment, p is 2.

In some embodiments of the Formulae above, q is 0. In anotherembodiment, q is 1. In yet another embodiment, q is 2.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is N. In yet another embodiment, X₁ is C, X₂is N and R₁ is OH. In another embodiment, X₁ is C, X₂ is N, R₁ is OH,and R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈. In anotherembodiment, X₁ is C, X₂ is N, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl,heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀,wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more R₈, and R₅ is H. In yet another embodiment,X₁ is C, X₂ is N, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl,(C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl,aryl, cycloalkyl, and heterocyclyl are optionally substituted with oneor more R₈, R₅ is H, and R₅, is H. In another embodiment, X₁ is C, X₂ isN, R₁ is OH, R₂ is (C₁-C₅) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈, R₅ is H,R₅, is H and R₆ is H. In yet another embodiment, X₁ is C, X₂ is N, R₁ isOH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈, R₅ is H,R_(5′) is H, R₆ is H and R₄ is (C₁-C₆) alkyl, aryl or heteroaryloptionally substituted with one or more R₁₂. In another embodiment, X₁is C, X₂ is N, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈)cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moreR₈, R₅ is H, R_(5′) is H, R₆ is H, R₄ is (C₁-C₆) alkyl, aryl orheteroaryl optionally substituted with one or more R₁₂, and R₁₂ is(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, halogen, —O-aryl, or —O— heteroaryloptionally substituted with one or more R₁. In another embodiment, X₁ isC, X₂ is N, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈)cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moreR₈, R₅ is H, R_(5′) is H, R₆ is H and R₄ is (C₁-C₆) alkyl, aryl orheteroaryl optionally substituted with one or more R₁₂. In anotherembodiment, X₁ is C, X₂ is N, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl,heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀,wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more R₈, R₅ is H, R_(5′) is H, R₆ is H, R₄ is(C₁-C₆) alkyl, aryl or heteroaryl optionally substituted with one ormore R₁₂, R₁₂ is (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, halogen, —O-aryl, or—O-heteroaryl optionally substituted with one or more R₁₃, and R₁₃ is(C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆)haloalkoxy, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl,and heteroaryl are substituted with one or more substituentsindependently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅, —OH, —CN,—C(O)R₁₄, or —NR₁₄R₁₅. In yet another embodiment, X₁ is C, X₂ is N, R₁is OH, R₂ is (C₁-C₅) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈, R₅ is H,R_(5′) is H, R₆ is H, R₄ is (C₁-C₆) alkyl, aryl or heteroaryl optionallysubstituted with one or more R₁₂, R₁₂ is (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substitutedwith one or more R₁₃, and two R₃ together when on adjacent carbons forma heterocyclyl ring optionally substituted with one or more R₁₆, two R₁₃together when on adjacent carbons form a heteroaryl ring optionallysubstituted with one or more R₁₆, or two R₁₃ together with the carbon towhich they are attached can form a spiroheterocyclyl optionallysubstituted with one or more R₁₆.

In some embodiments of the Formulae above, X₁ is C. In anotherembodiment, X₁ is C and X₂ is CH. In yet another embodiment, X₁ is C, X₂is CH and R₁ is OH. In another embodiment, X₁ is C, X₂ is CH, R₁ is OH,and R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈. In anotherembodiment, X₁ is C, X₂ is CH, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl,heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀,wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more R₈, and R₅ is H. In yet another embodiment,X₁ is C, X₂ is CH, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl,(C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl,aryl, cycloalkyl, and heterocyclyl are optionally substituted with oneor more R₈, R₅ is H, and R_(5′) is H. In another embodiment, X₁ is C, X₂is CH, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈)cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moreR₈, R₅ is H, R_(5′) is H and R₆ is H. In yet another embodiment, X₁ isC, X₂ is CH, R₁ is OH, R₂ is (C₁-C₅) alkyl, aryl, heteroaryl, (C₃-C₈)cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moreR₈, R₅ is H, R₅ is H, R₆ is H and R₄ is (C₁-C₆) alkyl, aryl orheteroaryl optionally substituted with one or more R₁₂. In anotherembodiment, X₁ is C, X₂ is CH, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl,heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀,wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more R₈, R₅ is H, R_(5′) is H, R₆ is H, R₄ is(C₁-C₆) alkyl, aryl or heteroaryl optionally substituted with one ormore R₁₂, and R₁₂ is (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, halogen, —O-aryl,or —O-heteroaryl optionally substituted with one or more R₁. In anotherembodiment, X₁ is C, X₂ is CH, R₁ is OH, R₂ is (C₁-C₈) alkyl, aryl,heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀,wherein alkyl, aryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more R₈, R₅ is H, R_(5′) is H, R₆ is H and R₄ is(C₁-C₆) alkyl, aryl or heteroaryl optionally substituted with one ormore R₁₂. In another embodiment, X₁ is C, X₂ is CH, R₁ is OH, R₂ is(C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl, heterocyclyl,—NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, and heterocyclylare optionally substituted with one or more R₈, R₅ is H, R_(5′) is H, R₆is H, R₄ is (C₁-C₆) alkyl, aryl or heteroaryl optionally substitutedwith one or more R₁₂, R₁₂ is (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, halogen,—O-aryl, or —O-heteroaryl optionally substituted with one or more R₁₃,and R₁₃ is (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy, halogen,(C₁-C₆) haloalkoxy, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, or —CN, wherein alkyl, cycloalkyl, aryl, heterocyclyl,and heteroaryl are substituted with one or more substituentsindependently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅, —OH, —CN,—C(O)R₁a, or —NR₁₄R₁₅. In yet another embodiment, X₁ is C, X₂ is N, R₁is OH, R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more R₈, R₅ is H,R₅, is H, R₆ is H, R₄ is (C₁-C₆) alkyl, aryl or heteroaryl optionallysubstituted with one or more R₁₂, R₁₂ is (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, halogen, —O-aryl, or —O-heteroaryl optionally substitutedwith one or more R₁₃, and two R₁₃ together when on adjacent carbons forma heterocyclyl ring optionally substituted with one or more R₁₆, two R₁₃together when on adjacent carbons form a heteroaryl ring optionallysubstituted with one or more R₁₆, or two R₁₃ together with the carbon towhich they are attached can form a spiroheterocyclyl optionallysubstituted with one or more R₁₆.

Non-limiting illustrative compounds of the invention include:

-   5-{[4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (1-1);-   4-({4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)benzonitrile    (I-10);-   1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-(5-methyl-5,6-dihydropyrrolo    [3,4-c]pyrazol-1(4H)-yl)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1000);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5-methyl-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1001);-   2-(4-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetamide    (I-1002);-   5-((1-((2R,4S)-1-acryloyl-4-methylazetidine-2-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1003);-   5-{[1-(4-{2,5-diazabicyclo[2.2.1]heptan-2-yl}benzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    trifluoroacetic acid salt (I-1005);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1006);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(1-methylpiperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1007);-   1-(3-(3-(dimethylamino)propyl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1008);-   3-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(piperidin-1-ylmethyl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one    (I-1009);-   3-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-7-[4-fluoro-3-(piperidin-1-ylmethyl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1010);-   (S)-5-(1-(1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1013);-   6-{[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]oxy}pyridine-3-carbonitrile    (I-1014);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-methylpyrazin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1015);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(2-methylpyrimidin-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1016);-   5-({4-hydroxy-1-[(1r,4r)-4-[(2-fluoropyridin-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1017);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-{[6-(azetidin-1-yl)pyridin-2-yl]oxy}cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1018);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(5-methoxypyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1019);-   5-({4-hydroxy-1-[(1r,4r)-4-[(5-methoxypyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1020);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyrazin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1021);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(2-methylpyrimidin-5-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1022);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1023);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1024);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1025);-   5-({1-[(3R)-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1028);-   5-({1-[(3S)-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1029);-   5-({4-hydroxy-1-[2-(1,2,3,4-tetrahydronaphthalen-1-yl)acetyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-103);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(pyridin-3-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1030);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(pyridin-3-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1031);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(5-fluoropyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1032);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(5-fluoropyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1033);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,3s)-3-[(pyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1034);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,3r)-3-[(pyridin-2-yl)amino]cyclobutanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1035);-   5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1036),-   5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1037);-   7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1038);-   Syn-5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    isomer A (I-1039a);-   Anti-5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    isomer B (I-1039b);-   5-({4-hydroxy-1-[4-(phenoxymethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-104);-   7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1040);-   7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1041);-   1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1042);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1043);-   1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1045);-   1-(3-((3,3-difluorocyclobutyl)methoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1046);-   1-{3-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1047),-   5-({4-hydroxy-1-[3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-105);-   5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1052);-   5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1058);-   5-[(4-hydroxy-1-{4-[(1-methylpyrrolidin-3-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1059);-   4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-phenylbenzene-1-sulfonamide    (I-106);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1060);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1061);-   5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1062);-   5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1063);-   5-({4-hydroxy-1-[(1s,3s)-3-(pyridin-2-yloxy)cyclobutanecarbonyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1064);-   1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-cyclopropylurea    (I-1065);-   4-[(1-{5-[(cyclopropylmethyl)amino]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1066);-   7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1067);-   N-[(1r,4r)-4-[(4-[[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidin-1-yl)carbonyl]cyclohexyl]acetamide    (I-1068);-   5-((4-hydroxy-1-((1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl)    piperidin-4-yl)methyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-1069);-   4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methy    1-N-phenylbenzene-1-sulfonamide (I-107);-   1-(4-bromophenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1070);-   5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1071);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(cyclopropylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1072);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(cyclopropylmethyl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1073);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(cyclopropylmethyl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1074);-   N-[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methy    1}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]cyclopropanecarboxamide    (I-1075);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-3-carboxamide    (I-1076);-   7-(4-fluorophenyl)-3-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1077);-   7-(4-fluorophenyl)-3-{[4-hydroxy-1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1078);-   3-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1079);-   4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methyl-N-phenylbenzamide    (I-108);-   1-[3-(4-acetylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1080);-   4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1,6,4-thiomorpholine-1,1-dione    (I-1081);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroquinolin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1082);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1083);-   2-[1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)piperidin-3-yl]acetonitrile    (I-1084);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[2-(4-methylpiperazin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1085);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[2-(pyridin-2-yloxy)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1086);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3,4-tetrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1087);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-imidazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1088);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1089);-   4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-phenylbenzamide    (I-109);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1090);-   1-(4-chlorophenyl)-5-{[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1091);-   1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-imidazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1092);-   1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1093);-   1-(4-chlorophenyl)-5-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1095);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1096),-   1-(4-chlorophenyl)-5-[[1-([3-[2-(dimethylamino)ethoxy]phenyl]carbonyl)-4-hydroxypiperidin-4-yl]methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1097);-   1-(4-chlorophenyl)-5-[(1-{3-[3-(dimethylamino)propoxy]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1098);-   1-(4-chlorophenyl)-5-[(1-[[4-(1,5-dimethyl-1H-imidazol-2-yl)phenyl]carbonyl]-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1099);-   2-(3-{5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)acetic    acid (I-11),-   N-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}benzamide    (I-110);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methylpyrazine-2-carboxamide    (I-1100);-   1-(4-chlorophenyl)-5-({1-[4-(1,2-dimethyl-1H-imidazol-5-yl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1101);-   5-{[1-(4,4-di    fluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1102);-   5-({1-[(3S)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1103);-   5-({1-[(3R)-4,4-difluoro-3-phenylbutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1104);-   5-{[1-(4-benzyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1108);-   N-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}benzenesulfonamide    (I-111);-   5-{[1-(3-benzyl-5-methyl-1,2-thiazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1110);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(difluoromethoxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1112),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyrazin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1113);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-5-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1114);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-methoxycyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1115);-   Syn-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    isomer A (I-1116a);-   Syn-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    isomer b (I-1116b),-   1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(1-methy 1    cyclopropanecarbonyl)    piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1117);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1118);-   1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)    piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1119);-   5-({4-hydroxy-1-[3-(1,3-thiazol-2-yl)butanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-112);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzamide    (I-1120);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzamide    (I-1121);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzamide    (I-1122);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-fluorobenzamide    (I-1123);-   7-(4-fluorophenyl)-3-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1124);-   3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1125);-   3-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1126);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[3-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1127);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1128);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1129);-   5-{[1-(2-chloro-4-phenoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-113);-   1-(4-chlorophenyl)-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1130);-   1-(4-chlorophenyl)-5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1131);-   1-(4-chlorophenyl)-5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1132);-   1-{4-[(3,3-difluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-133);-   1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1134);-   1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1135);-   5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1136);-   1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)    piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1137),-   4-hydroxy-4-[(1-{4-[(3R)-3-methoxypyrrolidin-1-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide    (I-1138),-   5-({4-hydroxy-1-[(3S)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1139);-   5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1140);-   5-((4-Hydroxy-1-(4-(4-hydroxycyclohexyloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-1141);-   5-((4-hydroxy-1-(4-(1-methylazetidin-3-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-1142);-   5-((4-Hydroxy-1-(4-(oxetan-3-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-1143);-   5-({4-hydroxy-1-[4-(oxan-4-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1144);-   5-((4-hydroxy-1-(4-(piperidin-4-yloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-1145);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1146);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(morpholin-4-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1147);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-ethylbutyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1148);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1149);-   5-{[4-hydroxy-1-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-115);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(cyclopropylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1150);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[(1-methylpiperidin-3-yl)methyl]amino}phenyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1151);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzene-1-sulfonamide    (I-1152);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(cyclopropylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1153);-   1-[3-(cyclohexylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1154);-   1-[3-(benzylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1155);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-phenylethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1156);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2,2-dimethylpropyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1157);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-3-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1158);-   5-({1-[(3R)-4,4-difluoro-3-(4-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1159);-   5-[(1-{3-[benzyl(methyl)amino]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-116);-   5-{[4-hydroxy-1-(4-{[5-(2-hydroxyethoxy)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1160);-   1-[4-(cyclohexylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1186);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-phenylethyl)amino]phenyl}-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1187);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2,2-dimethylpropyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1188);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(pyridin-3-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1189);-   5-[(1-{4-[benzyl(methyl)amino]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-119);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(1H-pyrazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1190);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(6-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1191),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1192);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1193);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(morpholin-4-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1194);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-ethylbutyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1195);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1196);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[(1-methylpiperidin-3-yl)methyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1197);-   5-{[1-(3-benzyl-1-methy)-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1161);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1-methyl-3-[(1R)-1-phenyl    ethyl]-1H-pyrazole-4-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1162);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1-methyl-3-[(1S)-1-phenyl    ethyl]-1H-pyrazole-4-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1163);-   5-{[1-(3-benzyl-5-methyl-1,2-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1164);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1165);-   1-(4-chlorophenyl)-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1166);-   1-(4-chlorophenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1167);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1168);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-imidazo[1,2-a]pyrimidin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1169);-   5-({4-hydroxy-1-[3-(1,2,3,4-tetrahydroquinolin-1-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-117);-   5{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{5H,6H,7H,8H-imidazo[1,2-a]pyrimidin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1170),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1171);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1172);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1173);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1174);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-methyl-5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1175);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{2-methyl-5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1176);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1177),-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{5H,6H,7H,    8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1178);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1179);-   5-{[1-(1-acetylpiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1180),-   5-[(1-{bicyclo[1.1.1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1181);-   1-[4-(cyclopentylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1182);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1183);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(5-methoxypyridine-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1184);-   5-[(1-{3-aminobicyclo[1,1,1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1185);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(oxan-4-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1198);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrrolidin-1-yl)phenyl]-1-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1199);-   5-({4-hydroxy-1-[4-(1,2,3,4-tetrahydroisoquinolin-2-yl)benzoyl]piperidin-4-yl}methyl)-1-methy    1-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-12);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1200);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1201);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolol[3,4-d]pyrimidin-4-one    (I-1202);-   1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)piperidine-4-carbonitrile    (I-1203);-   1-(4-[benzyl(methyl)amino]phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1204);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-phenylpiperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1205);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1206);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1207);-   N-[1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)piperidin-4-yl]acetamide    (I-1208);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1209);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1,2,3,4-tetrahydroisoquinolin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1210);-   1-[4-(4-acetylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1211);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridazin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1212);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2,4-dichlorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1213);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1214);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1H-indazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1215);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{8-oxa-2-azaspiro[4.5]decan-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1216);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{8-oxa-2-azaspiro[4.5]decan-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1217);-   5-{[1-(1-cyclopropylpiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1218);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{3-phenylbicyclo[1.1.1]pentane-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1219);-   5-[(1-{4-[(4aR,8aS)-decahydroisoquinolin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-122);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{pyrazolo[1,5-a]pyridine-3-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1221);-   5-({1-[5-(difluoromethoxy)pyridine-2-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1223);-   5-[(1-{6-aminospiro[3.3]heptane-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1224);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1225);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-piperidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1226);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-pyrrolidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1227);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-piperidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1228);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-pyrrolidine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1229);-   5-({4-hydroxy-1-[4-(1,2,3,4-tetrahydroquinolin-1-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-123);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(phenylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1230);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(phenylamino)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1231);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-4-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1232);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(pyridin-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1233);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1234),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1235);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1236);-   1-{4-[(2,1,3-benzoxadiazol-4-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1237);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1238);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(3-phenyl-1,2,4-thiadiazol-5-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1239);-   5-{[4-hydroxy-1-(4-{methyl[(2-methylphenyl)methyl]amino}benzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-124);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(1,3-thiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1240);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(5-methyl-1,2-oxazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1241);-   1-{4-[(4-tert-butyl-1,3-thiazol-2-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1242);-   1-{4-[(1,3-benzothiazol-6-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1243);-   1-{4-[(5-tert-butyl-1H-pyrazol-3-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methy    1]-1H,4H, 5H-pyrazolo[3,4-d]pyri mi di n-4-one (I-1244);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[1-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1245);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(pyridin-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1246);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[4-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1247);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(1H-pyrazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1248);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(6-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1249);-   5-({4-hydroxy-1-[4-(thiomorpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-125);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(2-methoxypyridin-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1250);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl}-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1251);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[3-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1252);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[2-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1253);-   6-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-3-carbonitrile    (I-1254);-   4-({1-[4-(cyanomethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1255);-   4-hydroxy-4-({1-[4-(2-methoxyethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N,N-dimethylpiperidine-1-carboxamide    (I-1256);-   1-{3-[(1,3-benzothiazol-6-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1257);-   1-{3-[(5-tert-butyl-1H-pyrazol-3-yl)amino]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1258);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1259);-   5-({4-hydroxy-1-[4-(1-phenoxyethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-126);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1260);-   4-({1-[5-(cyclopentylamino)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1261);-   4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{5-[(2-phenylethyl)amino]pyridin-3-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1262);-   4-hydroxy-N,N-dimethyl-4-{[1-(5-{[2-(morpholin-4-yl)ethyl]amino}pyridin-3-yl)-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-1263);-   4-hydroxy-N,N-dimethyl-4-({1-[5-(morpholin-4-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1264);-   4-({1-[5-(4-cyanopiperidin-1-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1265);-   4-hydroxy-N,N-dimethyl-4-[(1-{5-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1266);-   4-({1-[5-(1,1-dioxo-1,6,4-thiomorpholin-4-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1267);-   4-hydroxy-N,N-dimethyl-4-{[1-(5-{8-oxa-2-azaspiro[4.5]decan-2-yl}pyridin-3-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-1268);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[5-(piperazin-1-yl)pyridin-3-yl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1269);-   5-[(1-{4-[1-(4-fluorophenoxy)ethyl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-127);-   4-({1-[5-(3-fluorophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1270);-   4-({1-[5-(4-fluorophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1271);-   4-[(1-{5-[4-(dimethylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1272);-   4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{5-[4-(pyrrolidine-1-carbonyl)phenyl]pyridin-3-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1273);-   4-({1-[5-(3,4-dimethoxyphenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1274);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[5-(pyridin-3-yl)pyridin-3-yl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1275);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[3-(morpholin-4-yl)phenyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1276),-   6-[(4-{5-[(I-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-3-carbonitrile    (I-1277);-   5-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)amino]pyridine-2-carbonitrile    (I-1278),-   6-({4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)pyridine-2-carbonitrile    (I-128);-   4-[(1-{5-[3-(dimethylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1280);-   4-hydroxy-N,N-dimethyl-4-[(1-{5-[3-(methylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1281);-   4-hydroxy-4-{[1-(5-{3-[(2-hydroxyethyl)carbamoyl]phenyl}pyridin-3-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-N,N-dimethylpiperidine-1-carboxamide    (I-1282);-   4-hydroxy-N,N-dimethyl-4-({1-[5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1283),-   1-[4-(benzyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1284);-   1-[3-(benzyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1285);-   4-({1-[4-(cyclopentyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1286);-   1-[4-(cyclopentyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1287);-   1-[3-(cyclopentyloxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1288);-   4-({1-[4-(cyclopropylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1289);-   6-({4-[4-hydroxy-4-({1-methy 1-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methoxy)pyrazine-2-carbonitrile    (I-129),-   1-[4-(cyclopropylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1290);-   1-[3-(cyclopropylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1291);-   4-({1-[4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1292);-   4-hydroxy-4-[(1-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide    (I-1293);-   4-({1-[4-(carbamoylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1294);-   4-({1-[4-(cyclobutylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1295);-   4-hydroxy-N,N-dimethyl)-4-({1-[4-(3-methylbutoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1296);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(2,2,2-trifluoroethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1297);-   4-hydroxy-N,N-dimethyl-4-[(1-{4-[(1-methylpiperidin-2-yl)methoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1298);-   4-[(1-{4-[(4-cyanophenyl)methoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1299);-   5-({4-hydroxy-1-[4-(phenylamino)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-13);-   4-[(1-{4-[(3-cyanophenyl)methoxy]phenyl}-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1300);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(pyridin-3-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1301);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(pyridin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1302);-   4-hydroxy-N,N-dimethyl-4-({1-[4-(oxan-4-ylmethoxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1303);-   4-hydroxy-N,N-dimethyl-4-[(1-{4-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1304);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1305);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1306);-   2-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetamide    (I-1307);-   2-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetamide    (I-1308);-   1-[4-(cyclobutylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1309);-   5-[(1-{4-[4-(dimethylamino)piperidin-1-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-131);-   1-[3-(cyclobutylmethoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1310);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(3-methylbutoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1311);-   1-[3-(2,2-dimethylpropoxy)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1312);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-methylpiperidin-2-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1313);-   5-[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl)-1-{3-[(1-methylpiperidin-2-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1314);-   4-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile    (I-1315);-   4-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile    (I-1316);-   1-{3-[(4-chlorophenyl)methoxy]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1317);-   3-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxymethyl]benzonitrile    (I-1318);-   3-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenoxymethyl]benzonitrile    (I-1319);-   2-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetonitrile    (I-1320);-   2-[3-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy]acetonitrile    (I-1321);-   4-hydroxy-N,N-dimethyl-4-[(1-{5-[4-(methylcarbamoyl)phenyl]pyridin-3-yl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1322);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1324);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1325);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1326);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[2-(morpholin-4-yl)-2-oxoethoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1327);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{3-[(2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1328);-   4-({1-[6-(3-cyanophenyl)pyridin-3-yl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1329);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzamide    (I-1330);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-phenylacetamide    (I-1331);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(3-methyl-1,2-oxazol-5-yl)acetamide    (I-1332),-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzamide    (I-1333);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-fluorobenzamide    (I-1334);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxybenzamide    (I-1335);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-4-carboxamide    (I-1336);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-1,3-thiazole-4-carboxamide    (I-1337);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(oxan-4-yl)acetamide    (I-1338);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxyacetamide    (I-1339);-   N-(3-{5-[(I-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanecarboxamide    (I-1340);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide    (I-1341);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,3-thiazole-5-carboxamide    (I-1342),-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(dimethylamino)acetamide    (I-1343);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-6-methylpyridine-3-carboxamide    (I-1344);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-fluoropyridine-2-carboxamide    (I-1345);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-2-carboxamide    (I-1346);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide    (I-1347);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(methylamino)benzamide    (I-1348);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-(methylamino)benzamide    (I-1349);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxypyridine-3-carboxamide    (I-1350);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide    (I-1351);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methyl-1,3-thiazole-5-carboxamide    (I-1352);    N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(dimethylamino)acetamide    (I-1353);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-6-methylpyridine-3-carboxamide    (I-1354);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-fluoropyridine-2-carboxamide    (I-1355);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1,1-dioxo-1,6,4-thiomorpholin-4-yl)acetamide    (I-1356);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(morpholin-4-yl)acetamide    (I-1357);-   (2S)—N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpyrrolidine-2-carboxamide    (I-1358);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpiperidine-2-carboxamide    (I-1359);-   5-({4-hydroxy-1-[(3R)-3-methoxy-3-phenylpropanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-136);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-carboxamide    (I-1360);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1H-pyrazol-1-yl)acetamide    (I-1361);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-difluorocyclobutane-1-carboxamide    (I-1362);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(2-methoxyethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1363);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(2-methoxyethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1364);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyridin-3-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1365);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyridin-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1366);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyridin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1367);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(pyridin-2-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1368);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(3-methyl-1,2-oxazol-5-yl)acetamide    (I-1369);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzamide    (I-1370);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-fluorobenzamide    (I-1371);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxybenzamide    (I-1372);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-4-carboxamide    (I-1373);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-1,3-thiazole-4-carboxamide    (I-1374);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(oxan-4-yl)acetamide    (I-1375);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxyacetamide    (I-1376);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanecarboxamide    (I-1377);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzamide    (I-1378);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzamide    (I-1379);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-fluorobenzamide    (I-1380);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-3-carboxamide    (I-1381);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methylpyrazine-2-carboxamide    (I-1382);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyridine-2-carboxamide    (I-1383);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methy    1]-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(methylamino)benzamide    (I-1384),-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-(methylamino)benzamide    (I-1385);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methoxypyridine-3-carboxamide    (I-1386);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1387);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1388);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(1,3-thiazol-2-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1389);-   5-{[1-(1-benzyl-1,2,3,4-tetrahydroquinoline-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-139),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(5-methyl-1,2-oxazol-3-yl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1390);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1,1-dioxo-1,6,4-thiomorpholin-4-yl)acetamide    (I-1391),-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(morpholin-4-yl)acetamide    (I-1392);-   (2S)—N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpyrrolidine-2-carboxamide    (I-1393);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-methylpiperidine-2-carboxamide    (I-1394);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-carboxamide    (I-1395);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-(1H-pyrazol-1-yl)acetamide    (I-1396);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-difluorocyclobutane-1-carboxamide    (I-1397);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-[methyl(phenyl)amino]acetamide    (I-1398);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-2-(morpholin-4-yl)propanamide    (I-1399);-   5-{[(3S,4R)-1-benzoyl-4-hydroxy-3-methoxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-14);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-5-methyl-1,2-oxazole-4-sulfonamide    (I-1400);-   4-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1401);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(oxan-4-ylmethyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1402);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methylbenzene-1-sulfonamide    (I-1403);-   2-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1404);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzene-1-sulfonamide    (I-1405);-   3-chloro-N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1406);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzene-1-sulfonamide    (I-1407);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylbenzene-1-sulfonamide    (I-1408);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-[methyl(phenyl)amino]acetamide    (I-1409);-   5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-141);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methyl-2-(morpholin-4-yl)propanamide    (I-1410);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)acetamide    (I-1411);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzamide    (I-1412);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-phenylacetamide    (I-1413);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolol[3,4-d]pyrimidin-1-yl}-N-(oxetan-3-yl)benzamide    (I-1414);-   3-(5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-phenylbenzamide    (I-1415);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(pyridin-3-yl)benzamide    (I-1416);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methanesulfonamide    (I-1417);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanesulfonamide    (I-1418);-   N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)oxane-4-sulfonamide    (I-1419);-   5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-142);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzenesulfonamide    (I-1420);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,5-dimethyl-1,2-oxazole-4-sulfonamide    (I-1421);-   4-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1422);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methoxybenzene-1-sulfonamide    (I-1423);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-4-methylbenzene-1-sulfonamide    (I-1424);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-2-methylbenzene-1-sulfonamide    (I-1425);-   2-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1426);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methoxybenzene-1-sulfonamide    (I-1427);-   3-chloro-N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzene-1-sulfonamide    (I-1428);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-fluorobenzene-1-sulfonamide    (I-1429);-   5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-143);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylbenzene-1-sulfonamide    (I-1430),-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methanesulfonamide    (I-1431);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)cyclopropanesulfonamide    (I-1432),-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(4-fluorophenyl)methanesulfonamide    (I-1433);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1434);-   3-cyclopentyl-1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methy    1]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1435);-   5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1436);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methy    1}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1437);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-phenylurea    (I-1438);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-phenylurea    (I-1439);-   5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-144);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(4-fluorophenyl)urea    (I-1440);-   1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(4-methylphenyl)urea    (I-1442);-   1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(3-methoxypropyl)urea    (I-1443);-   1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(3-methoxypropyl)urea    (I-1444);-   1-[4-(4-fluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1445);-   1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-cyclopropylurea    (I-1446);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methy    1]-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(pyridin-3-yl)urea    (I-1447);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(pyridin-3-yl)urea    (I-1448);-   1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(thiophen-3-yl)urea    (I-1449);-   5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-145),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-hydroxypiperidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1450);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1451);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-methylbenzamide    (I-1452);-   N-benzyl-3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzamide    (I-1453);-   N-cyclobutyl-3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzamide    (I-1454);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(4-fluorophenyl)methyl]benzamide    (I-1455);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(dimethylamino)ethyl]benzamide    (I-1456);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(3-methyloxetan-3-yl)methyl]benzamide    (I-1457);-   4-({1-[4-fluoro-3-(3-fluoroazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1458);-   4-({1-[4-fluoro-3-(3-hydroxyazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1459);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-methyl-1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1460);-   4-({1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1461),-   4-hydroxy-N,N-dimethyl-4-{[4-oxo-1-(4-{[2-(propan-2-yl    oxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-1462);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-fluorophenyl)benzamide    (I-1463);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(1,3-thiazol-2-yl)benzamide    (I-1464);-   3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(5-methyl-1,2-oxazol-3-yl)benzamide    (I-1465);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1466);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholine-4-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1467);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino)    piperidine-1-carbonyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1468);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methylpiperazine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1469);-   5-{[1-(4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-147);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-fluoroazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1470);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{imidazo[1,2-a]pyrazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1471);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1472);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1473);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1474);-   5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1475);-   5-{[1-(1H-1,2,3-benzotriazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1476);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1477);-   5-{[1-(1,3-benzothiazole-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1478);-   N-tert-butyl-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide    (I-1479);-   3-cyclopentyl-1-(4-{5-[(I-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1480);-   1-cyclohexyl-3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1481);-   1-cyclohexyl-3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1482);-   1-benzyl-3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1483);-   1-benzyl-3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-1484);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-methylbenzamide    (I-1485),-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(4-fluorophenyl)methyl]benzamide    (I-1486);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(dimethylamino)ethyl]benzamide    (I-1487);-   4-{5-[(i-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[(3-methyloxetan-3-yl)methyl]benzamide    (I-1488);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(oxetan-3-yl)benzamide    (I-1489);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-phenylbenzamide    (I-1490),-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(pyridin-3-yl)benzamide    (I-1491);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-fluorophenyl)benzamide    (I-1492);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(1,3-thiazol-2-yl)benzamide    (I-1493);-   4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(5-methyl-1,2-oxazol-3-yl)benzamide    (I-1494);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholine-4-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1495);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(dimethylamino)    piperidine-1-carbonyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1496);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1497);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,3-difluoropyrrolidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1498);-   N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)pyrrolidine-1-carboxamide    (I-1499);-   5-{[1-(1-benzyl-1H-pyrrole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-150);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(oxan-4-yl)urea    (I-1500);-   1-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-dimethylurea    (I-1501);-   propan-2-yl    N-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)carbamate    (I-1502);-   4-[(1-{4-[(8aS)-octahydropyrrolo[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1503);-   4-hydroxy-4-({1-[4-(4-hydroxy-4-methylpiperidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N,N-dimethylpiperidine-1-carboxamide    (I-1504);-   5-{[1-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1505);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(5-methoxy-1-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1506);-   5-{[1-(3,4-dihydro-2H-1-benzopyran-6-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1507);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-methylcyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1508);-   4-hydroxy-4-[(1-{4-[(3S)-3-methoxypyrrolidin-1-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-N,N-dimethylpiperidine-1-carboxamide    (I-1509);-   5-{[1-(4-fluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-151);-   5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1510);-   5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1511);-   5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1512);-   5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1513);-   5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1514);-   5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1516);-   5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1517);-   5-{[4-hydroxy-1-(5-methyl-1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1518);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1519);-   1-cyclopropyl-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-152);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1520);-   1-(4-chlorophenyl)-5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1521);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1522);-   1-(4-chlorophenyl)-5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1523);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1524);-   4-[(1-{4-[(9aS)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1525);-   4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl]piperidine-1-carboxamide    (I-1526);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1527),-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1528);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1529);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-153);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1530),-   5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1531);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1532);-   5-{[1-(4,4-difluorobutanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1533);-   2-[4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)phenyl]-1,6,2-thiazolidine-1,1-dione    (I-1534);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1535);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(4-hydroxypiperidin-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1536);-   5-({1-[2-(difluoromethoxy)acetyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1537);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1538);-   4-hydroxy-N,N-dimethyl-4-({1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-1539);-   5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-154);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1540);-   4-[(1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1541);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1542);-   4-hydroxy-N,N-dimethyl-4-{[4-oxo-1-(4-{[2-(piperidin-1-yl)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-1543),-   4-[(1-{4-[(3,3-dimethylcyclobutyl)amino]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1544);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1545);-   4-[(1-{4-[(8aR)-octahydropyrrolo[1,2-a]piperazin-2-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1546-   5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1547);-   4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(1H-pyrazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1548-   5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1549);-   5-{[4-hydroxy-1-(1-methyl-1H-imidazole-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-155);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1550);-   5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1551);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1552);-   5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1553);-   5-({4-hydroxy-1-[2-(oxan-4-yl)acetyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1554);-   5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1555);-   5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1556);-   5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1557);-   5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1558),-   5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1559);-   5-{[1-(4-cyclopropylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-156);-   5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1560);-   1-[3-(4-fluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1561),-   5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methy    1}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1562);-   5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1563);-   5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1564);-   5-{[4-hydroxy-1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1565),-   5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1566);-   5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methy    1}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1567);-   5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1568);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1569);-   5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-157);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(oxan-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1570);-   5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrindin-4-one    (I-1572);-   5-[(4-hydroxy-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1573);-   5-[(4-hydroxy-1-{2H,3H-pyrazolo[3,2-b][1,3]oxazole-6-carbonyl}piperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1574);-   5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1575),-   1-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-3,3-dimethylurea    (I-1576-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[);4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1577);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1578),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1579);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-158);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(trifluoromethyl)    pyrimidin-2-yl]oxy}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1580);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(1H-pyrazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1581);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1582),-   4-hydroxy-N,N-dimethyl-4-[(4-oxo-1-{4-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carboxamide    (I-1583);-   1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1584);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-1,2,3-triazol-1-yl)piperidine-1-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1585);-   1-[3-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1587);-   1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1588),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxetan-3-yloxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1589);-   5-{[4-hydroxy-1-(3-hydroxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-159);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxan-4-ylmethoxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1590);-   5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenyl    phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1591);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1593);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[3-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1594);-   1-(4-chlorophenyl)-5-([4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1595);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{pyrazolo[1,5-a]pyridine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1596);-   1-(4-chlorophenyl)-5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1597);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1598),-   1-(4-chlorophenyl)-5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1599);-   5-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-1,2-dihydropyridin-2-one    (I-160);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrindin-4-one    (I-1600);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1601);-   5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1602);-   5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1603);-   5-{[1-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1604);-   5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1605);-   5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1606);-   5-{[1-(dimethyl-1,3-thiazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1607);-   5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1608);-   5-{[4-hydroxy-1-(1H-indole-6-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1609);-   5-{[4-hydroxy-1-(1H-indazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-161);-   5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1610);-   5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1611);-   5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1612);-   5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1613);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1614);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1615);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1616);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1617),-   1-(4-{7-azaspiro[3.5]nonan-7-yl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1618);-   1-(4-{3-azaspiro[5.5]undecan-3-yl}phenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1619);-   5-{[1-(3-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-162);-   1-(4-{3-azaspiro[5.5]undecan-3-yl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1620),-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1621);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{9-methyl-3,9-diazaspiro[5.5]undecan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1622);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1623);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1624);-   5-[(1-acetyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-chlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1625);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1626);-   1-(4-chlorophenyl)-5-{[1-(5-cyclopropyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolol[3,4-d]pyrimidin-4-one    (I-1628);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(3-methyl-1,2-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1629);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{imidazo[1,2-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1630);-   1-(4-chlorophenyl)-5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1631);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1632);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1633);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(5-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1634);-   1-(4-chlorophenyl)-5-{[1-(1,3-dimethyl-1H-pyrazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1635);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(morpholin-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1636);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(morpholin-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1637);-   rel-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1638);-   1-{4-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1639);-   N-{4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}methanesulfonamide    (I-164);-   1-{4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1640);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1641);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(oxetan-3-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1642);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1643);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(3-{8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1644-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(3,4,5-trimethylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1645);-   1-{3-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1646);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1647);-   1-(4-chlorophenyl)-5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1648);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1649);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(4-hydroxypiperidin-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1650);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1651);-   5-{[1-(2-amino-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-chlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1652);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1653);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-4-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1654);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1655);-   1-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(propan-2-yl)urea    (I-1656);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1657);-   5-{[4-hydroxy-1-(4-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1658);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1659);-   5-({4-hydroxy-1-[3-(hydroxymethyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-166);-   5-{[4-hydroxy-1-(5-methoxypyridine-2-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1660);-   5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1661);-   5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1662);-   5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1663);-   5-[(4-hydroxy-1-{imidazo[1,5-a]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1664);-   5-({4-hydroxy-1-[4-(1H-1,    2,3-triazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1665);-   4-({1-[3-(4-chloro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-1666);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(oxan-4-yloxy)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1667),-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1668);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1669);-   5-{[4-hydroxy-1-(2-hydroxybenzoyl)piperidin-4-yl]methy    1}-1-phenyl-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-167);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyri    midi n-4-one (I-1670);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1671);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1672);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1673),-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[3-(2-hydroxypropan-2-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1674);-   1-[3-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1675),-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(2-hydroxypropan-2-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1676);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(3-hydroxyazetidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1677);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(3-hydroxyazetidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1678);-   1-[4-(3-fluoroazetidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1679);-   5-{[4-hydroxy-1-(1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-168);-   1-[3-(3-fluoroazetidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1680);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1681);-   5-{[    1-(4-{1,4-diazabicyclo[3.2.2]nonan-4-yl}benzoyl)4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1682);-   5-[(1-{4-[(9aS)-octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-fluorophenyl)-1-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1683);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1684);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1685);-   1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1686);-   5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1687);-   5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1688);-   1-{3-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1689);-   5-{[4-hydroxy-1-(l    H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-169);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1690);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[4-(oxetan-3-yl)piperidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1691);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl)-1-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1692);-   1-{4-[3-(difluoromethyl)-4-methylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1693);-   1-{3-[3-(difluoromethyl)-4-methylpiperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1694);-   rel-3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1695);-   rel-3-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-7-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1696);-   rel-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1697);-   rel-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1698);-   1-{3-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1699);-   5-{[1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-17);-   N-[(2R)-2-benzyl-3-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-3-oxopropyl]ethene-1-sulfonamide    (I-170-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1700);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1701);-   1-{3-[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1702);-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-N-[(4-fluorophenyl)methyl]-4-hydroxypiperidine-1-carboxamide    (I-1703);-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-phenylpiperidine-1-carboxamide    (I-1704);-   N-(4-fluorophenyl)-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide    (I-1705);-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(3-methoxypropyl)piperidine-1-carboxamide    (I-1706);-   N-cyclopropyl-4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxamide    (I-1707),-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(pyridin-3-yl)piperidine-1-carboxamide    (I-1708);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1709);-   N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]ethene-1-sulfonamide    (I-171);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1710);-   5-{[4-hydroxy-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl]methyl}-1-[4-(3-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1711);-   1-{4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1712-   5-{[4-hydroxy-1-(3-methy 1 oxetane-3-carbonyl)piperidin-4-yl]methy    1}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1713);-   5-{[4-hydroxy-1-(1-methyl    cyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{3-oxa-9-azaspiro[5.5]undecan-9-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1714);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-(4-{l-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1715);-   5-{[4-hydroxy-1-(1-methyl cyclopropanecarbonyl)piperidin-4-yl]methy    1}-1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1716);-   5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methy    1}-1-{4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1717);-   1-(4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1718);-   5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1719);-   3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzamide    (I-172);-   1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)    piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1720);-   1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1721);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1722);-   1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1723);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{l-methyl-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1724);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methylpyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1725);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(5-methylpyridin-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1726);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1727);-   1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1728);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1729);-   N-{4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}ethene-1-sulfonamide    (I-173);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methy    1}-1-[4-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1730);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-{3-[3-(oxan-4-yl)azetidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1732);-   1-[4-(4-chloro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1733);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1734);-   5-[(1-{4-[(8aS)-octahydropyrrolo[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1735);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{pyrazolo[1,5-a]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1736);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1737);-   1-[4-(1,2-benzoxazol-4-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1738);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-hydroxy-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1739);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1740);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1741);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1742);-   1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methy    1}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-1743);-   4-{4-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-1H-pyrazol-1-yl}-1,6-thiane-1,1-dione    (I-1744),-   3-{4-[4-(5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]-1H-pyrazol-1-yl}-1,6-thietane-1,1-dione    (I-1745);-   1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1746);-   1-{4-[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1747);-   1-{3-[(1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1748);-   1-{4-[(1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1749);-   5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-175);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl)-1-(3-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1750);-   1-[3-(5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]piperidine-4-carbonitrile    (I-1751);-   1-[4-(5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]piperidine-4-carbonitrile    (I-1752);-   5-({1-[4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1753);-   1-[4-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)    piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1754);-   1-(4-{6-azaspiro[2.5]octan-6-yl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1755);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1756);-   2-[2-(dimethylamino)ethoxy]ethyl    4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate    (I-1757);-   2-(1H-imidazol-1-yl)ethyl    4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate    (I-1759);-   5-({4-hydroxy-1-[(3S)-3-(l    H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-176);-   1-methylpiperidin-4-yl    4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carboxylate    (I-1762);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1763);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl-1H-indazol-6-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1764);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-methyl-1H-indazol-7-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1765);-   1-[4-(1,2-benzoxazol-5-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1766);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1767),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{1H-pyrrolo[3,2-b]pyridin-5-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1768);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-(trifluoromethyl)pyrimidin-4-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1769);-   (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1770);-   (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1771);-   7-(4-fluorophenyl)-3-((4-hydroxy-1-((1r,4r)-4-((1-methyl-1H-pyrazol-3-yl)oxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1772);-   7-(4-fluorophenyl)-3-((4-hydroxy-1-((1s,4s)-4-((1-methyl-1H-pyrazol-3-yl)oxy)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1773);-   (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1774);-   (S)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1775);-   (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1776);-   (R)-3-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-morpholinophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one    (I-1777);-   1-(4-((3,3-difluoro-1-methylcyclobutyl)methoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1778);-   (S)—N-(2-benzyl-3-(4-hydroxy-4-((4-oxo-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidin-1-yl)-3-oxopropyl)ethenesulfonamide    (I-1779);-   1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1800);-   1-(4-(3,3-difluorocyclobutoxy)phenyl)-5-((4-hydroxy-1-(J-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-1801);-   5-({4-hydroxy-1-[(3R)-3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-177);-   5-({4-hydroxy-1-[(3S)-3-(1H-pyrrol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-178);-   4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzamide    (I-179);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(2-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-18);-   5-({4-hydroxy-1-[4-(methoxymethyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-180);-   N-{3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}acetamide    (I-181);-   4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methylbenzene-1-sulfonamide    (I-182);-   4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]-N-methylbenzamide    (I-184);-   5-[(1-cyclohexanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-189);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-19);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-190);-   5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-191);-   5-{[4-hydroxy-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-192);-   5-{[1-(3-ethoxypropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-193);-   5-[(1-cyclobutanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-194);-   5-[(1-cyclopentanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-195);-   5-{[1-(2,2-dimethylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-196);-   5-{[1-(3,5-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-197);-   5-{[4-hydroxy-1-(3-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-198);-   5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-199);-   5′{[1-(2-fluoro-4-phenylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-2);-   5-({1-[3-(aminomethyl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-20);-   5-{[1-(3,4-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-200);-   5-{[1-(3-fluoro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-201);-   5-{[¹-(2,3-dihydro-1-benzofuran-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-202);-   5-{[1-(3,5-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-203);-   5-{[1-(3-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-204);-   5-{[1-(2-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-205);-   5-{[1-(2-fluoro-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-206);-   5-{[1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-207);-   5-{[1-(2,5-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-208);-   5-{[1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-209);-   5-{[1-(3-chloro-4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-210);-   5-{[1-(3-chloro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-211);-   5-{[1-(4-chloro-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-212);-   5-{[1-(3,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-213);-   5-{[1-(3-chloro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-214),-   5-{[4-hydroxy-1-(2-methylbenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-215);-   5-{[1-(2,5-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-216);-   5-{[1-(2,4-dimethylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-217);-   5-{[1-(5-chloro-2-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-218);-   5-{[1-(4-chloro-2-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-219);-   3-{5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}benzoic    acid (I-22);-   5-{[1-(2,3-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methy    1}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-220);-   5-{[1-(2,5-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-221);-   5-{[1-(2,4-dimethoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-222);-   5-{[1-(2,5-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-223);-   5-{[1-(2,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-224);-   5-{[4-hydroxy-1-(pyridine-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-225);-   5-{[1-(4-chloro-3-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-226),-   5-{[4-hydroxy-1-(5-methylpyrazine-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-227);-   5-{[4-hydroxy-1-(pyridine-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-228),-   5-{[1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-229);-   5-({1-[4-(cyclopropylamino)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-23);-   5-{[1-(dimethyl-1,3-thiazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-230);-   5-{[4-hydroxy-1-(1,2,3-thiadiazole-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-231);-   5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-232);-   5-{[1-(2-amino-5-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-233);-   5-{[1-(2-amino-3-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-234);-   5-{[4-hydroxy-1-(5-methyl-1,2-oxazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-235);-   5-{[4-hydroxy-1-(5-methyl-1H-pyrazole-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-236);-   5-{[4-hydroxy-1-(4-methyl-1,3-thiazole-5-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-237);-   5-{[4-hydroxy-1-(6-methylpyridine-3-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-238);-   5-({4-hydroxy-1-[2-(trifluoromethyl)pyrimidine-5-carbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-239);-   5-{[1-(5-fluoropyridine-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-240);-   5-{[1-(5-ethyl-1,3-oxazole-4-carbonyl-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-241);-   5-{[1-(3-fluoro-4-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-242);-   5-{[1-(3-fluoro-2-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-243);-   5-{[1-(5-fluoro-2-methylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-244);-   5-{[1-(dimethyl-1,2-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-245);-   5-{[1-(2,3-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-246);-   5-{[4-hydroxy-1-(1H-indole-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-247);-   5-{[1-(4,4-dimethylpentanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-248),-   5-{[4-hydroxy-1-(oxane-4-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-249);-   1-(4-tert-butylphenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-25);-   5-{[4-hydroxy-1-(1-methyl-1H-pyrrole-2-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-250);-   5-{[1-(3,3-difluorocyclobutanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyri    mi di n-4-one (I-251);-   5-{[4-hydroxy-1-(2-phenyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-252);-   N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]prop-2-ynamide    (I-259);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(2,4,6-trimethylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-26);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(2,4-dichlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-264);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-266);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-267);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-268);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(propan-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-27);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-271);-   4-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]benzoic    acid (I-272);-   5-({4-hydroxy-1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-273);-   5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-274);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-276);-   5-({4-hydroxy-1-[1-(trifluoromethyl)cyclopropanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-277);-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-279);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-28);-   5-{[1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-280);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-281);-   5-{[1-(4-chloroquinoline-7-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-282);-   5-{[1-(4-cyclopropoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-283),-   4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-methylpiperidine-1-carboxamide    (I-284);-   5-{[1-(2-chloropyridine-4-carbonyl)-4-hydroxypiperidin-4-yl]methy    1}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-287);-   5-{[1-(2,5-dichloropyridine-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-288);-   5-[(1-{bicyclo[1.1.1]pentane-1-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-289);-   1-cyclohexyl-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-29);-   5-({4-hydroxy-1-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-290);-   5-({4-hydroxy-1-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-291);-   2-cyano-N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]acetamide    (I-292);-   5-({1-[4-(1,1-difluoroethyl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-294);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-296);-   5-({4-hydroxy-1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-3);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(pyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-30);-   5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    Enantiomer A (I-301a),-   5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    Enantiomer B (I-301b);-   5-{[1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-302);-   5-{[1-(3-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-303);-   5-{[1-(4-cyclopropylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-304);-   5-{[1-(3-chloro-1-methyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-305);-   5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-306);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-307);-   5-{[1-(3-fluoro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-308);-   5-{[1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-309);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-methanesulfonylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-31);-   5-{[1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-310);-   5-{[1-(3-chloro-4-methoxybenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-311);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-312);-   5-{[1-(dimethyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-313);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-314);-   5-({1-[2-(dimethylamino)-1,3-oxazole-5-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-315);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-316);-   5-{[1-(2,4-dichlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyri    mi di n-4-one (I-317);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(pyridin-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-32);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3,4-dichlorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-33);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-330);-   4-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide    (I-332);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(pyrrolidine-1-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-333);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,4-dimethoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-334);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-335);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,5-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-337);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile    (I-339);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-34);-   4-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile    (I-340);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-342);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-phenylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-344);-   1-[3-(2-chlorophenyl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolol[3,4-d]pyrimidin-4-one    (I-345);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-346);-   1-[3-(3-chlorophenyl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-347);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-fluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-348);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(4-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-349),-   1-(4-chlorophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-35);-   4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide    (I-350);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(pyrrolidine-1-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-351);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,4-dimethoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-352);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(2,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-354);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,4-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-355);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3,5-difluorophenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-357);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile    (I-359);-   4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)benzonitrile    (I-360);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(dimethylamino)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-361);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-363),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(dimethyl-1,2-oxazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-364);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-365);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-366);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-367);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(morpholin-4-yl)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-368);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(dimethylamino)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-369);-   N-[2-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)phenyl]methanesulfonamide    (I-370);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(2-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-371);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-hydroxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-372);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(5-fluoropyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-373);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-[3-(dimethylamino)phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-374);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[4-(dimethylamino)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-375);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(dimethyl-1,2-oxazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-377);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-378);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrimidin-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-379);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-38);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-380);-   4-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-methylbenzamide    (I-381);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[5-hydroxy-2-(trifluoromethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-382);-   N-[2-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)phenyl]methanesulfonamide    (I-383);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(2-methanesulfonylphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-384);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-hydroxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-385);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[6-(dimethylamino)pyridin-3-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-386-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-387);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(morpholine-4-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-388);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-389),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[5-fluoro-2-(hydroxymethyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-390);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(3-fluoro-5-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-391);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide-1-sulfonamide    (I-392);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide    (I-394);-   3-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-(2-hydroxyethyl)benzamide    (I-395);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1-methyl-1H-indazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-396);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(cyclopropylmethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-397);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(pyrolidin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-399);-   4-hydroxy-N-methyl-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-N-(4-phenylphenyl)piperidine-1-carboxamide    (I-4);-   N-[(1r,3r)-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]cyclobutyl]ethane-1-sulfonamide    (I-40);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-400);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-401);-   1-[3-(5-chloropyridin-3-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-401);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(morpholine-4-carbonyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-402);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[5-fluoro-2-(hydroxymethyl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-403);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(3-fluoro-5-methoxyphenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-404);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzene-1-sulfonamide    (I-405);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1H-indol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-406);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N,N-dimethylbenzamide    (I-407);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-methylbenzamide    (I-408);-   3-(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-N-(2-hydroxyethyl)benzamide    (I-409);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1-methyl-1H-indazol-5-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-410);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(cyclopropylmethoxy)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-411);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[3-(pyrrolidin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-413);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-415);-   1-(4-{[cyclohexyl(ethyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-416);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(morpholin-4-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-417);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(pyridine-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-418);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(morpholin-4-yl)pyridine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-419);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-420);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(pyri    dine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-421);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[6-(trifluoromethyl)pyridine-3-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-422);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperidin-4-yl}methyl)-1-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-423);-   4-hydroxy-N-methyl-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-425);-   5-{[(3S,4S)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-426);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-({[2-(dimethylamino)ethyl](methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-427);-   N-{1-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-4-yl}acetamide    (I-428);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-430);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-431);-   1-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidine-4-carbonitrile    (I-432);-   1-(4-{[benzyl(methyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-433),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{([(2-methoxyethyl)(methyl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-434);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-435);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[methyl(2-methylpropyl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-436);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-437);-   1-{4-[(4-acetylpiperazin-1-yl)methyl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-438);-   4-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]-1λ⁶,4-thiomorpholine-1,1-dione    (I-439);-   5-[(1R)-1-[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]ethyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-44);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-({[(6-ethylpyridin-3-yl)methyl](methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-440);-   2-{l-[(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-3-yl}acetonitrile    (I-441);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[cyclopropyl(oxan-4-yl)amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-442);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{8-oxa-2-azaspiro[4.5]decan-2-ylmethyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-443);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(pyrrolidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-444);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperidin-1-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-445);-   1-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidine-4-carbonitrile    (I-446);-   1-(3-{[benzyl(methyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-447);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-({[2-(dimethylamino)ethyl](methyl)amino}methyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrindin-4-one    (I-448);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[(2-methoxyethyl)(methyl)    amino]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-449);-   N-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)ethene-1-sulfonamide    (I-45);-   N-{1-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-4-yl}acetamide    (I-450);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-451);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{[methyl(2-methyl    propyl)amino]methyl}phenyl)-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-452);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-453);-   1-{3-[(4-acetylpiperazin-1-yl)methyl]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-454);-   4-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]-Iλ⁶,4-thiomorpholine-1,1-dione    (I-455);-   2-{l-[(3-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)methyl]piperidin-3-yl}acetonitrile    (I-456);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(3-{8-oxa-2-azaspiro[4.5]decan-2-ylmethyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-457);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(oxan-4-yl)acetyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-458);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(2-methoxyacetyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-459);-   N-[(2R)-1-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]ethene-1-sulfonamide    (I-46);-   3-[1-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-1-oxopropan-2-yl]-1,3-oxazolidin-2-one    (I-461);-   5-{[1-(4,4-difluorocyclohexanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-462);-   5-{([1-(2-cyclopropylacetyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-463);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-464);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(6-methoxypyridine-3-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-465);-   1-(4-fluorophenyl)-5-{[1-(6-fluoropyridine-3-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-466);-   5-({4-hydroxy-1-[4-(1-hydroxycyclopropyl)benzoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-467);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1-hydroxycyclopropyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-468);-   5-{[(3R,4S)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-469);-   5-{[1-(3-chloro-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-47);-   4-hydroxy-N-methyl-4-{[4-oxo-1-(6-phenylpyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-470);-   1-[3-(Cyclopentylamino)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-471);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-472),-   1-(4-Fluorophenyl)-5-[(4-hydroxy-1-{8-oxabicyclo[3.2.1]octane-3-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-473),-   4-({1-[4-(Benzyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-474);-   4-((1-(4′,6-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-475);-   N-(3-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)acetamide    (I-476);-   N-(3-(5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide    (I-477);-   1-(3-(5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-isopropylurea    (I-478);-   5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-479);-   3-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-48),-   1-(4-Fluorophenyl)-5-((4-hydroxy-1-(1H-pyrrolo[3,2-c]pyridine-2-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-480);-   4-{[1-(4-Fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(propan-2-yl)piperidine-1-carboxamide    (I-481);-   N-(3,3-Dimethylcyclobutyl)-4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxamide    (I-482);-   1-(4-Chlorophenyl)-5-{[4-hydroxy-1-(1H-indole-2-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-483);-   (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-484);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{imidazo[1,2-a]pyridin-8-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-485);-   3-(Pyrrolidin-1-yl)propyl    4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate    (I-486);-   5-[(1-{4-[(8aR)-octahydropyrrolo[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-487);-   5-{[4-Hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-488);-   1-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]phenyl}-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-489);-   3-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-7-(4-fluorophenyl)-6-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-49);-   1-(4-{2,2-Difluoro-7-azaspiro[3.5]nonan-7-yl}phenyl)-5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-490);-   1-{4-[(5-Chloropyridin-2-yl)oxy]phenyl}-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-491);-   1-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3,3-dimethylurea    (I-492);-   Propan-2-yl    N-(4-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)carbamate    (I-493);-   3-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-1-(oxan-4-yl)urea    (I-494);-   1-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-(oxetan-3-yl)urea    (I-495);-   4-({1-[4-(3,3-dimethylazetidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-496),-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-497);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-498);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-499);-   1-(3-{[cyclohexyl(ethyl)amino]methyl}phenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-5);-   4-Hydroxy-N,N-dimethyl-4-{[4-oxo-1-(4-phenoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-500);-   4-{[1-(4-Fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-(oxan-4-yl)piperidine-1-carboxamide    (I-501);-   (4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-502);-   (3-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)urea    (I-503);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(methylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-504);-   5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(dimethylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-505);-   1-(4-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylurea    (I-506),-   1-(3-{5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}phenyl)-3-methylurea    (I-507);-   4-{[1-(4-{3,9-Diazaspiro[5.5]undecan-3-yl}phenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-1]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-508);-   1-(4-Fluorophenyl)-5-[(4-hydroxy-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-509);-   7-[3-(aminomethyl)phenyl]-3-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-51);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[3-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-510);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-513);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-514);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-515);-   5-({1-[3-(difluoromethoxy)cyclobutanecarbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-516);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-517);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-518);-   5-({1-[(3S)-3-{2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-519);-   3-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-7-(5-fluoropyridin-2-yl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-52);-   5-({1-[(3R)-3-{2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-520);-   5-({1-[(3S)-3-{1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-521),-   5-({1-[(3R)-3-{1H,4H,5H,6H-cyclopenta[c]pyrazol-1-yl}butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-522);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-523);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-524);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-{octahydrocyclopenta[c]pyrrol-2-yl}butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-525);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-526);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(2R)-1,1,1-trifluoro-2-hydroxy    propan-2-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-527),-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(2S)-1,1,1-trifluoro-2-hydroxy    propan-2-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-528);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyrrolidin-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-529);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(morpholin-4-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-530);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-531);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-2-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-532);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(1-methylpiperidin-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-533);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-534);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-535);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(piperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-536);-   5-({1-[3-fluoro-4-(4-methylpiperazin-1-yl)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-537);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-538);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-539);-   4-{3-chloro-4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}-N,N-dimethylbenzamide    (I-54);-   5-{[1-(1-benzyl-1H-indole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-540);-   5-{[1-(1-benzyl-1H-pyrazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-541);-   5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-542);-   5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-543);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-544),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-545);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-546);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[5-(pyridin-2-yloxy)pyridine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-547);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(1H-pyrazol-1-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-548);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(1H-pyrazol-1-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-549);-   5-[(1-{2-chloro-4-[4-(piperidine-1-carbonyl)phenyl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-55);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{2H,3H-pyrazolo[3,2-b][1,3]oxazol-7-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-550);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-551);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-552);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{4-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidin-3-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-553);-   5-{[1-(2-amino-4-chlorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-554);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(morpholin-4-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-555);-   5-{[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-556);-   5-{[1-(5-benzyl-1,3-oxazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-557);-   1-(4-fluorophenyl)-5-[(1-{1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-558);-   5-[(1-{1-[(2,6-difluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-559);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-56);-   1-(4-fluorophenyl)-5-[(1-{l-[(3-fluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methy    1]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (I-560);-   1-(4-fluorophenyl)-5-[(1-{l-[(2-fluorophenyl)methyl]-1H-pyrrole-2-carbonyl}-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-561);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(1-methyl-1H-pyrazol-4-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-562),-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(5-methyl-1,2-oxazol-3-yl)oxy]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-563),-   1-[4-(4-fluorophenyl)phenyl]-5-{[4-hydroxy-1-(piperazine-1-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-564);-   N-[(1s,3s)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-enamide    (I-568);-   N-[(1S,3R)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclopentyl]prop-2-enamide    (I-569);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-57);-   N-[(1R,3S)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclopentyl]prop-2-enamide    (I-570);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2R)-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-574);-   N-[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methy    1}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]prop-2-enamide (I-575);-   N-[(1s,4s)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]prop-2-enamide    (I-576);-   N-[(1s,3s)-3-[2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-2-oxoethyl]cyclobutyl]prop-2-ynamide    (I-578);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2S)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-579);-   1-benzyl-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-58);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2R)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-580);-   N-[(1r,3r)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]acetamide    (I-582);-   5-((1-(3-(aminomethyl)benzoyl)-4-hydroxypiperidin-4-yl)    methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one    (I-585);-   5-((1-(4-(1-(aminomethyl)cyclopropyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one hydrochloride (I-586);-   N-((1-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5    (4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)cyclopropyl)methyl)acetamide    (I-587);-   N-methyl-N-[(1r,3r)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide    (I-589);-   1-tert-butyl-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-59);-   1-tert-butyl-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-60);-   N-methyl-N-[(1s,3s)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide    (I-600);-   1-(4-fluorophenyl)-5-((4-hydroxy-1-(3-((3-hydroxy-3-methyl-pyrrolidin-1-yl)methyl)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-601);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{3-[1-(pyrrolidin-1-yl)ethyl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-602);-   5-([1-[(5-benzyl-1H-pyrazol-4-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-603);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-604);-   1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-(1-methylpiperidin-4-yl)    benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-605),-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[4-(4-methylpiperazin-1-yl)    phenyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-606);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-{octahydro-1H-pyrido[1,2-a]piperazin-2-yl}benzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-607);-   5-[(1-{4-[(9aR)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-608);-   5-[(1-{4-[(9aS)-octahydro-1H-pyrido[1,2-a]piperazin-2-yl]benzoyl}-4-hydroxypiperidin-4-yl)methyl]-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-609);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(propan-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-61);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[4-(pyridin-2-yloxy)piperidin-1-yl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-610);-   5-((1-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1    (4H)-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-611);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[4-(hydroxymethyl)-1H-pyrazol-1-yl]benzoyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-612);-   5-((1-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-613);-   1-(4-fluorophenyl)-5-(1-[4-hydroxy-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl]ethyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-614);-   1-(4-fluorophenyl)-5-(1-[4-hydroxy-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl]ethyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-615);-   5-(1-(l-(3-(aminomethyl)benzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one hydrochloride (I-616);-   5-[(4-hydroxypiperidin-4-yl)methyl]-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-617);-   4-Hydroxy-4-[[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-N,N-dimethylpiperidine-1-carboxamide    (I-618);-   4-Hydroxy-4-[[1-(4-hydroxyphenyl)-4-oxo-1H,4H,5H-pyrazolo    [3,4-d]pyrimidin-5-yl]methyl]-N,N-dimethylpiperidine-1-carboxamide    (I-619);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(propan-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-62),-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-620);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(3-methoxyphenyl)-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-621);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-622);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-623);-   5-(1-(1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)ethyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-624);-   5-{l-[4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl]ethyl}-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-625);-   1-(3-bromo-4-fluorophenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-626);-   1-(4-fluoro-3-methoxyphenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-627-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(6-fluoropyridin-3-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-628);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-cyclopropylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-629);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-3-methyl-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-63);-   1-(4-bromophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-630);-   1-(3-bromo-4-chlorophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-631);-   1-(4-fluoro-3-hydroxyphenyl)-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-632);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-fluoro-3-(3-methoxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-633);-   5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-634);-   1-(3-Amino-4-fluorophenyl)-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-635);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-fluoro-3-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-636);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-637);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-638);-   1-[4-fluoro-3-(morpholin-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-639);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-3-methyl-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-64);-   1-(4-fluoro-3-(hydroxymethyl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-640);-   5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-fluoro-3-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-641);-   1-[4-fluoro-3-(hydroxymethyl)phenyl]-5-({4-hydroxy-1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-642);-   1-(Biphenyl-4-yl)-5-((4-hydroxy-1-(2-morpholinooxazole-5-carbonyl)    piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one    (I-643);-   5-({1-[4,4-di    fluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-644);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-645);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-646);-   5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-648),-   5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-649);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-65);-   5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-650);-   1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-652);-   1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-653);-   1-[4-(4-fluorophenyl)phenyl]-5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-654);-   4-([1-[4-(4-fluorophenyl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxy-N-methylpiperidine-1-carboxamide    (I-655);-   5-((1-(1-acryloylazetidine-2-carbonyl)-4-hydroxypiperidin-4-yl)    methyl)-1-(biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one    (I-657);-   N-[(1r,3r)-3-(4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carbonyl)cyclobutyl]prop-2-ynamide    (I-658);-   5-({4-hydroxy-1-[(2S)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-659);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-66);-   5-({4-hydroxy-1-[(2R)-2-methyl-1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-660);-   pyrrolidin-3-ylmethyl    4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxylate    (I-661);-   N-(4-fluoropyrrolidin-3-yl)-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-662);-   N-[(3R)-4-fluoropyrrolidin-3-yl]-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-663);-   N-[(3S)-4-fluoropyrrolidin-3-yl]-4-hydroxy-4-{[4-oxo-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidine-1-carboxamide    (I-664);-   5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(2-(hydroxymethyl)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-665);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(hydroxymethyl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-666);-   5-([4-hydroxy-1-[(morpholin-4-yl)carbonyl]piperidin-4-yl]methyl)-1-[3-(hydroxymethyl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-667);-   1-[3-(Aminomethyl)-4-phenylphenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-668),-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{3-[(dimethylamino)methyl]-4-phenylphenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-669);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-[3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-67);-   5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-[[2-(propan-2-yloxy)ethyl]amino]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-670);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{[2-(propan-2-yloxy)ethyl]amino}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-671);-   5-([4-hydroxy-1-[(4-methylphenyl)carbonyl]piperidin-4-yl]methyl)-1-[4-[4-(2-hydroxyethoxy)-1H-pyrazol-1-yl]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-672);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-673);-   5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(2′-(2-(dimethylamino)ethylamino)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-674);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-[4-(pyrrolidin-3-yloxy)phenyl]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-675);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[2-(dimethylamino)ethoxy]-3-fluorophenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-676);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{2-[2-(dimethylamino)ethoxy]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-677);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(1-methylpyrrolidin-3-yl)oxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-678);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}phenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-679);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-68);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}phenyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-680);-   5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(1-(2,2-difluoroethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-681);-   4-hydroxy-N,N-dimethyl-4-({1-[4-(oxan-4-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-682);-   4-[(1-{4-[1-(2,2-difluoroethyl)piperidin-4-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-683);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-684);-   5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(6-(3-(methylamino)pyrrolidin-1-yl)pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-685);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[(3S)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-686);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-687);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[3-(methylamino)pyrrolidin-1-yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-688);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[(3S)-3-(methylamino)pyrrolidin-1-yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-689);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-69);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{4-[(3R)-3-(methylamino)    pyrrolidin-1-yl]phenyl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-690);-   1-[4-[3-(3-aminooxetan-3-yl)phenyl]phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-691),-   5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-[(1-methylazetidin-3-yl)oxy]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-692);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(4-fluorooxan-4-yl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-693),-   1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-694);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-695);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-696);-   1-(4-(4,4-difluorocyclohexyloxy)phenyl)-5-((4-hydroxy-1-(4-methylpiperazine-1-carbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-697);-   5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(2-(piperazin-1-yl)biphenyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4    (5H)-one (I-698);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-699);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-(pyridin-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-70);-   1-[4-(4,4-difluoropiperidin-1-yl)phenyl]-5-{[4-hydroxy-1-(4-methylbenzoyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-700);-   1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-701);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-(morpholin-4-yl)-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-702);-   5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-703);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(1-phenyl-1H-pyrazol-4-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-704);-   1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-705),-   4-((7-(4-fluorophenyl)-4-oxo-6-phenyl-4H-pyrrolo[2,3-d]pyrimidin-3    (7H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-706);-   1-[4-(dimethylamino)phenyl]-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-707);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-(pyridin-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-71);-   1-(4-(1H-1,2,3-triazol-1-yl)phenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-711);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-712);-   5-([1-[(4-Fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(1-hydroxycyclopropyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-713);-   5-{[(3R,4R)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-716);-   5-{[(3S,4R)-1-benzoyl-3-fluoro-4-hydroxypiperidin-4-yl]methyl}-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-717);-   1-(4-fluorophenyl)-5-((4-hydroxy-1-(4-((1-methyl-1H-pyrazol-3-yl)oxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-719);-   5-({4-hydroxy-1-[(3R)-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-72);-   5-(1-(l-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)-2-hydroxyethyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-720);-   8-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-8-hydroxyoctahydro-4H-quinolizin-4-one    (I-721);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-methoxycyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-722);-   4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)-1Ωω-thiane-1,1-dione    (I-723);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(4,5,6,7-tetrahydro-1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-724);-   1-(4-fluorophenyl)-5-{[4-hydroxy-1-(1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-725);-   5-{[1-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-726),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-727);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-728);-   5-{[4-hydroxy-1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-1-phenyl-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-4-one (I-73);-   5-({1-[(3R)-3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-731);-   5-({1-[(3S)-3-(3-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-732);-   5-({1-[(3R)-3-(4-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-733);-   5-({1-[(3S)-3-(4-chloro-1H-pyrazol-1-yl)-4,4-difluorobutanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-734);-   5-({1-[(3R)-4,4-difluoro-3-(4-methyl-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-735);-   5-({1-[(3S)-4,4-difluoro-3-(4-methyl-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-736);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[(1r,4r)-4-[(5-fluoropyridin-2-yl)oxy]cyclohexyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-737);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-[[(1s,4s)-4-[(5-fluoropyridin-2-yl)    oxy]cyclohexyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-738);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-739);-   5-({4-hydroxy-1-[4-(1H-imidazol-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-74);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-740);-   5-({4-hydroxy-1-[(1r,4r)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-741);-   5-({4-hydroxy-1-[(1s,4s)-4-[(6-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-742);-   5-({4-hydroxy-1-[(1r,4r)-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-743);-   5-({4-hydroxy-1-[(1s,4s)-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-744);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-1-methyl-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-745);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-1-methyl-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-746);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyrimidin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-747);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyrimidin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-748);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-749);-   5-({4-hydroxy-1-[4-(1H-1,2,3,4-tetrazol-1-ylmethyl)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-75);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-3-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-750);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-751);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-752);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-753);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-754);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(5-methyl-1,2-oxazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-755);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(5-methyl-1,2-oxazol-3-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-756);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-757),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-758);-   5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-759);-   5-{[1-(2-benzylbenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-76);-   5-({1-[(2R)-2-benzylazetidine-1-carbonyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-760);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-761);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{l-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-762),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-5-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-763);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-5-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-764);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-765);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-[(1-methyl-1H-pyrazol-3-yl)amino]cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-766);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(phenylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-767),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(phenylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-768),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(cyclopropylamino)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-769);-   5-({1-[3-(3-fluorophenyl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-77);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(3,3-difluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-770);-   1-(4-chlorophenyl)-5-[(1-[[2-(cyclopropylamino)-1,3-oxazol-5-yl]carbonyl]-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-771);-   1-(4-chlorophenyl)-5-{[4-hydroxy-1-(1-methyl-1H-pyrazole-4-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-772-   5-((1-(3-(3-aminopropoxy)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-774);-   5-((4-hydroxy-1-(1-methyl cyclopropanecarbonyl)piperidin-4-yl)    methyl)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-775);-   5-([1-[(2-Cyclopropyl-1,3-oxazol-5-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-776);-   (S)-1-(4-(hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)    methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-777);-   (R)-1-(4-(hexahydro-1H-pyrido    [1,2-a]pyrazin-2(6H)-yl)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-778);-   5-([1-[(2-cyclopropyl-1,3-oxazol-5-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-779);-   5-({1-[3-(4-fluorophenyl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-78);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-780);-   5-{[4-hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-781);-   5-{[4-hydroxy-1-(1-methylcyclobutanecarbonyl)piperidin-4-yl]methyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-782);-   (R)-5-((1-(cyclohexanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-783);-   1-(4-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-784);-   1-(4-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-785);-   1-(4-(4,4-Difluorocyclohexylamino)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropanecarbonyl)    piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-786);-   N-(4′-(4-((1-(4-ethynylphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)ethenesulfonamide    (I-787);-   5-([1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-788);-   5-([1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[3-(morpholin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-789);-   5-{[4-hydroxy-1-(2-methyl-4-phenylbutanoyl)piperidin-4-yl]methy    1}-1-methyl-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-79);-   1-(3-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3S)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (T-790);-   1-(3-{3-azabicyclo[3.1.0]hexan-3-yl}phenyl)-5-({1-[(3R)-4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-791);-   (R)-3-((1-(4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one    (I-792);-   (S)-3-((1-(4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one    (I-793);-   7-(4-fluorophenyl)-3-((4-hydroxy-1-(trans-4-((1-methyl-1H-pyrazol-5-yl)oxy)    cyclohexanecarbonyl)piperidin-4-yl)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one    (I-794);-   1-(4-ethylphenyl)-5-((4-hydroxy-1-(4-(1-methylpiperidin-4-yloxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-795);-   (R)-5-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-796);-   (S)-5-((1-(4,4-difluoro-3-(3-fluoro-1H-pyrazol-1-yl)butanoyl)-4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-797);-   5-([1-[(1-cyclopropyl-1H-pyrazol-4-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-cyclopropylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-798);-   1-(4-cyclopropylphenyl)-5-((4-hydroxy-1-(2-methyloxazole-5-carbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-799),-   5-{[1-(2-benzylcyclopropanecarbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-80),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(2S)-1-(prop-2-ynoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-803);-   1-(4-Fluorophenyl)-5-((4-hydroxy-1-(trans-4-(5-methylisoxazol-3-ylamino)    cyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-806);-   1-(4-Fluorophenyl)-5-((4-hydroxy-1-(cis-4-(5-methylisoxazol-3-ylamino)cyclohexanecarbonyl)    piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-807);-   5-{[4-hydroxy-1-(2-methoxy-3-phenylpropanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-81);-   4-{[1-(3-bromo-4-fluorophenyl)-4-oxo-1H,4H,    5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-810);-   4-{[1-(3-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-811);-   4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoic    acid (I-812);-   N-[(2R)-1-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]ethene-1-sulfonamide    (I-814);-   Anti-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    isomer A (I-815a);-   Syn-5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    isomer B (l-815b);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-((3-hydroxy-1-methylazetidin-3-yl)methoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-816);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-817);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-818);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(morpholin-4-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-819);-   5-{[4-hydroxy-1-(4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-82);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{1H,4H,6H,7H-pyrano[4,3-c]pyrazol-1-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-820);-   5-([1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-821);-   5-([1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(piperidin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-822);-   1-(3-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-823);-   1-[4-fluoro-3-(piperazin-1-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-824);-   5-({1-[4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-825);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-826);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-827);-   5-({1-[4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-828);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-829);-   2-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)acetonitrile    (I-83);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-830);-   5-({4-hydroxy-1-[1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-[3-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-831);-   5-({4-hydroxy-1-[1-(prop-2-enoyl)azetidine-2-carbonyl]piperidin-4-yl}methyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-832);-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-833),-   5-({1-[(3R)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-834);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-835);-   5-({1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-836);-   5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-837);-   5-({4-hydroxy-1-[(3S)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-838);-   5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-839);-   1-(2-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenyl}phenyl)cyclopropane-1-carbonitrile    (I-84);-   5-({4-hydroxy-1-[(3R)-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1-{4-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-840);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(3S)-pyrrolidin-3-yloxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-841);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-[4-[(3R)-pyrrolidin-3-yloxy]phenyl]phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-842);-   5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-843);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(4-methylpiperazin-1-yl)phenyl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-844);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-{6-[3-(methylamino)    pyrrolidin-1-yl]pyridin-3-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-845);-   1-(4-cyclobutylphenyl)-5-{[4-hydroxy-1-(2-methyl-1,3-oxazole-5-carbonyl)piperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-846);-   1-(4-cyclobutylphenyl)-5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-847);-   3-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-849);-   5-({1-[4-(4-chlorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-85);-   3-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-7-(4-fluorophenyl)-6-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one    (I-850);-   5-({1-[4-(difluoromethoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-851);-   5-({4-hydroxy-1-[(1r,4r)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-852);-   5-({4-hydroxy-1-[(1s,4s)-4-(pyridin-2-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-853);-   1-[4-(azetidin-1-ylmethyl)phenyl]-5-([1-[(3S)-4,4-difluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-854);-   1-[4-(azetidin-1-ylmethyl)phenyl]-5-([1-[(3R)-4,4-di    fluoro-3-(1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-855);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-[2-(dimethylamino)ethoxy]-4-phenylphenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-856);-   5-({1-[4-(4-fluorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-86);-   5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-phenylbutanoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-861);-   5-({1-[4-(4-bromophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-87);-   5-({4-hydroxy-1-[4-(4-hydroxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-88);-   5-({4-hydroxy-1-[4-(3-hydroxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-89);-   5-[(4-hydroxy-1-{4-[(pyrimidin-2-yloxy)methyl]benzoyl}piperidin-4-yl)methyl]-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-9);-   5-({1-[4-(3-chlorophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-90);-   5-({1-[4-(3-bromophenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-91);-   1-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-910);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-911);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3S)-4,4,4-trifluoro-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-912);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(3R)-4,4,4-trifluoro-3-(1H-pyrazol-1-yl)butanoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-913);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[2-(4-hydroxypiperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-915);-   5-({4-hydroxy-1-[2-(4-hydroxypiperidin-1-yl)-1,3-oxazole-5-carbonyl]piperidin-4-yl}methyl)-1-(4-phenylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-916);-   5-({4-hydroxy-1-[(1r,3r)-3-(pyridin-2-yloxy)cyclobutanecarbonyl]piperidin-4-yl}methyl)-1-(4-methyl    phenyl)-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-4-one (I-917);-   5-({1-[(3S)-4,4-difluoro-3-(4-fluoro-1H-pyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl}methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-918);-   1-(4-chlorophenyl)-5-({4-hydroxy-1-[4-(4H-1,2,4-triazol-4-yl)benzoyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-919);-   5-{[4-hydroxy-1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-92);-   1-(4-chlorophenyl)-5-[(4-hydroxy-1-{6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-920);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[1-methyl-3-(1H-pyrazol-1-ylmethyl)-1H-pyrazole-4-carbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-921);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(5-methyl-1,2-oxazol-3-yl)oxy]piperidine-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-922);-   1-(4-fluorophenyl)-5-[(4-hydroxy-1-{4-[(1-methyl-1H-pyrazol-4-yl)oxy]piperidine-1-carbonyl}piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-923);-   N-[(1r,4r)-4-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclohexyl]acetamide    (I-924),-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1s,4s)-4-(oxan-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-925);-   1-(4-fluorophenyl)-5-({4-hydroxy-1-[(1r,4r)-4-(oxan-4-yloxy)cyclohexanecarbonyl]piperidin-4-yl}methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-926);-   4-{[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-928);-   5-({4-hydroxy-1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-93);-   5-({4-hydroxy-1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-94);-   5-({4-hydroxy-1-[4-(3-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-95);-   N-[(1r,3r)-3-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide    (I-950);-   N-[(1R,2S)-2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidine-1-carbonyl)cyclobutyl]prop-2-ynamide    (I-952),-   N-[(1r,3r)-3-[2-(4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)-2-oxoethyl]cyclobutyl]prop-2-ynamide    (I-958);-   4-{4-[4-hydroxy-4-({1-methyl-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carbonyl]phenoxy}benzonitrile    (I-96);-   1-(3-aminophenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-964);-   1-(4-aminophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-965);-   4-((1-(4-fluoro-3-(piperazin-1-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-966);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(piperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-967);-   4-[(1-{4-[(3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl]phenyl}-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-968);-   1-[4-chloro-3-(morpholin-4-yl)phenyl]-5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-969);-   5-({1-[4-(3,4-dimethylphenoxy)benzoyl]-4-hydroxypiperidin-4-yl}methyl)-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-97);-   5-[(1-benzoyl-4-hydroxypiperidin-4-yl)methyl]-1-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-970);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3S)-3-methoxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-971);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-fluoro-3-[(3R)-3-methoxy-3-methylpyrrolidin-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-972);-   5-{5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-(4-methylpiperazin-1-yl)benzonitrile    (I-973);-   4-((1-(3-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide    (I-974);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-975);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-(4-{2H,4H,6H,7H-pyrano[4,3-c]pyrazol-2-yl}phenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-976);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(2-hydroxy    ethoxy)-1H-pyrazol-]-yl-1-phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-977);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[3-(morpholin-4-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-978);-   5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-(4-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-980);-   5-{[1-(2-cyclopropyl-1,3-oxazole-5-carbonyl)-4-hydroxypiperidin-4-yl]methyl}-1-{4-[(1-fluorocyclobutyl)methoxy]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-981);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-((1-hydroxycyclobutyl)methoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-982);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-methyl-1H-imidazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-983);-   1-[4-(1,5-dimethyl-1H-imidazol-2-yl)phenyl]-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-984);-   5-((1-(2-Cyclopropyloxazole-5-carbonyl)-4-hydroxypiperidin-4-yl)    methyl)-1-(4-(pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-985);-   5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-[4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-987);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-988),-   5-((1-(4-(difluoromethoxy)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-989);-   5-{[1-(3-cyclopropyl-3-phenylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-1-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-99);-   1-(4-fluoro-3-(hydroxymethyl)phenyl)-5-((4-hydroxy-1-(4-(pyrimidin-2-yloxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-990);-   4-hydroxy-4-((1-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-N,N-dimethylpiperidine-1-carboxamide    (I-992);-   5-{[1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl]methyl}-1-[3-(piperidin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one    (I-993);-   4-hydroxy-N,N-dimethyl-4-({4-oxo-1-[4-(piperidin-4-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidine-1-carboxamide    (I-994),-   (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    enantiomer A (I-995);-   (S)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,    enantiomer B (I-996);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one    (I-996a);-   (S)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)    phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, enantiomer A    (I-997);-   (R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)    phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, enantiomer B    (I-998);-   5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one    (I-998a); and-   1-[4-[(4-[[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidin-1-yl)carbonyl]phenyl]-1H-pyrazole-4-carboxylic    acid (I-999).

In another embodiment of the invention, the compounds of Formula (I) areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentinvention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Each compound herein disclosed includes all the enantiomersthat conform to the general structure of the compound. The compounds maybe in a racemic or enantiomerically pure form, or any other form interms of stereochemistry. The assay results may reflect the datacollected for the racemic form, the enantiomerically pure form, or anyother form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this invention. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present invention relates to compounds which are modulators of USP7.In one embodiment, the compounds of the present invention are inhibitorsof USP7.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present invention includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention can be synthesized by following the steps outlined inGeneral Schemes 1, 2, 3, and 4 which comprise different sequences ofassembling intermediates IIa, IIb, IIIa, IIIb, IIIx, IVa, IVb, IVx, Va,Vb, Vx, VIIx, and VIIIx. Starting materials are either commerciallyavailable or made by known procedures in the reported literature or asillustrated.

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates IIa, IIIa, IVa, and Va is outlined in General Scheme 1.Cyclization of a hydrazine hydrochloride (or the hydrazine) with a2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e.,triethylamine or N,N-diisopropylethylamine (DIPEA), in solvent, i.e.,ethanol, at elevated temperatures provides intermediate IIa.Intermediate IIIa is then prepared by cyclization of nitrile IIa andformic acid in the presence of a catalytic amount of water at anelevated temperature Alternatively, intermediate IIa can be obtained bytreating IIa with a strong acid, i.e., sulfuric acid, to obtain an amideintermediate which is then cyclized to the pyrazolo pyrimidine IIIa withtriethyl orthoformate and acetic anhydride at an elevated temperature.Nucleophilic addition of IIIa to atert-butyl-1,6-[3]-dioxa-8-azaspiro[2.7]decan-7-one intermediate in asolvent, i.e., dimethylformamide (DMF) at elevated temperature providesIVa. Deprotection of intermediate IVa using a strong acid such astrifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane (DCM)yields Va. Acylation of intermediate Va to produce a compound of Formula(I) where X₁ is C, can be accomplished by coupling of an acid understandard coupling conditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Va can be acylated with anacid chloride or carbamoyl chloride using a base, i.e., triethylamine orDIPEA, and optionally in solvent to produce a compound of Formula (I)where X₁ is C. For synthesis of a compound of Formula (I) where X₁ is Sor S(O), intermediate Va is treated with a sulfonyl chloride or asulfinic chloride and a base, i.e., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane,DMF to provide the desired product of Formula (I).

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

Alternatively, molecules of Formula (I) can be prepared usingintermediates IIa, IIIx, IVx, IVa, and Va as outlined in General Scheme2. Cyclization of a hydrazine hydrochloride (or the hydrazine) with a2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e.,triethylamine or N,N-diisopropylethylamine (DIPEA), in solvent, i.e.,ethanol, at elevated temperatures provides intermediate IIa. Hydrolysisof IIa using an acid (i.e., dilute hydrochloric acid) or a base (i.e.,sodium hydroxide solution) in a solvent (i.e., water) providescarboxylic acid IIIx. Coupling of the acid IIIx with amine VIIx understandard coupling conditions using a coupling reagent, i.e.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF provides IVx.Intermediate IVa is then prepared by cyclization of IVx and formic acidin the presence of a catalytic amount of water at an elevatedtemperature. Deprotection of intermediate IVa using a strong acid suchas trifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane (DCM)yields Va. Acylation of intermediate Va to produce a compound of Formula(I) where X₁ is C, can be accomplished by coupling of an acid understandard coupling conditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DTPEA), in a solvent, e.g., dichloromethane or DMF to provide compoundsof Formula (I). Alternatively, intermediate Va can be acylated with anacid chloride or carbamoyl chloride using a base, i.e., triethylamine orDIPEA, and optionally in solvent to produce a compound of Formula (I)where X₁ is C. For synthesis of a compound of Formula (I) where X₁ is Sor S(O), intermediate Va is treated with a sulfonyl chloride or asulfinic chloride and a base, i.e., triethylamine orN,N-diisopropylethylamine (DIPEA), in a solvent, i.e., dichloromethane,DMF to provide the desired product of Formula (I).

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

Molecules of Formula (I) can also be prepared using intermediates IIa,IIIx, and Vx as outlined above in General Scheme 3. Cyclization of ahydrazine hydrochloride (or the hydrazine) with a2-(ethoxymethylidene)propanedinitrile optionally using a base, i.e.,triethylamine or N,N-diisopropylethylamine (DIPEA), in solvent, i.e.,ethanol, at elevated temperatures provides intermediate IIa. Hydrolysisof IIa using an acid (i.e., dilute hydrochloric acid) or a base (i.e.,sodium hydroxide solution) in a solvent (i.e., water) providescarboxylic acid IIIx Coupling of the acid IIIx with amine VIIIx understandard coupling conditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF provides Vx.Cyclization of Vx and formic acid in the presence of a catalytic amountof water at an elevated temperature provides compounds of Formula (I).Alternatively, of compounds of Formula (I) can be obtained by treatingVx with a strong acid, i.e., sulfuric acid, to obtain an amideintermediate which is then cyclized to the pyrrolo pyrimidine of Formula(I) with triethyl orthoformate and acetic anhydride at an elevatedtemperature.

wherein R₂-R₆, X₁, m, and n are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates IIb, IIIb, IVb, and Vb is outlined in General Scheme 4.Treatment of Intermediate IIb with 1,4-diazabicyclo[2.2.2]octane(DABCO), a solvent, i.e., dioxane and/or water, and a base, i.e.,potassium carbonate or cesium carbonate, etc., at an elevatedtemperature provides intermediate IIIb. Nucleophilic addition of IIIb toa tert-butyl-1,6-[3]-dioxa-8-azaspiro[2.7]decan-7-one intermediate usinga base, i.e., potassium carbonate or cesium carbonate, etc., in asolvent, i.e., dimethylformamide (DMF) at elevated temperature providesIVb. Deprotection of intermediate IVb using a strong acid such astrifluoroacetic acid (TFA) in a solvent, i.e., dichloromethane (DCM)yields Vb. Acylation of intermediate Vb to produce a compound of Formula(I) where X₁ is CR₇, can be accomplished by coupling of an acid understandard coupling conditions using a coupling reagent, i.e.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, i.e., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF. Alternatively,intermediate Vb can be acylated with an acid chloride or carbamoylchloride using a base, i.e., triethylamine or DIPEA, and in a solvent,i.e., dichloromethane to produce a compound of Formula (I) where X₁ isC. For synthesis of compounds of Formula (I) where X₁ is S or S(O), Vbis treated with a sulfonyl chloride or a sulfinic chloride and a base,i.e., triethylamine or N,N-diisopropylethylamine (DIPEA), in a solvent,i.e., dichloromethane, DMF to provide the desired product of Formula(I).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the process described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formula shown above,the various groups R₂-R₅, R_(5′), R₆, X₁, X₂, m, n, and other variablesare as defined above, except where otherwise indicated. Furthermore, forsynthetic purposes, the compounds of General Schemes 1, 2, 3, and 4 aremere representative with elected radicals to illustrate the generalsynthetic methodology of the compounds of Formula (I) as defined herein.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of USP7. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of USP7 an effective amount thecompositions and compounds of Formula (I).

In another aspect, the present invention is directed to a method ofinhibiting USP7. The method involves administering to a patient in needthereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treating,preventing, inhibiting or eliminating a disease or disorder in a patientassociated with the inhibition of USP7, the method comprisingadministering to a patient in need thereof an effective amount of acompound of Formula (I). In one embodiment, the disease or disorder isselected from the group consisting of cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present invention also relates to the use of an inhibitor of USP7for the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or condition mediated by USP7,wherein the medicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or condition mediated by USP7, wherein themedicament comprises a compound of Formula (I).

Another aspect of the present invention relates to a compound of Formula(I) for use in the manufacture of a medicament for treating a diseaseassociated with inhibiting USP7.

In another aspect, the present invention relates to the use of acompound of Formula (I) in the treatment of a disease associated withinhibiting USP7.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treatinga neurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I).

Another aspect of the invention relates to a method of treating a viralinfection and disease. The method comprises administering to a patientin need thereof an effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treatingan inflammatory disease or condition. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

In one embodiment, the present invention relates to the use of aninhibitor of USP7 for the preparation of a medicament used in treatment,prevention, inhibition or elimination of a disease or disorderassociated with associated with cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of cancers including, but not limited to, liposarcoma,neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer, HumanPapilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroidor vaginal cancer or Epstein-Barr Virus-associated nasopharyngealcarcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkinlymphoma or diffuse large B-cell lymphoma.

In some embodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of USP7, MDM2 or MDM4relative to tissue-matched expression. In other embodiments, the patientis selected for the treatment based on tumor expression of wild typeTP53 or based on the tumor immune cell composition, specificallyelevated regulatory T lymphocytes, CD4+CD25+FoxP3+ T cells.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

For example, the change in the cell cycle or cell viability may beindicated by decreased tumor levels of MDM2 protein and/or increasedlevels of TP53, CDKNIA (p21, Cip1), PUMA or BAX or by increasedexpression of one or more p53 target genes. In one embodiment, the p53target genes include, but are not limited to, CDKNIA (p21, Cip1), BBC3(PUMA), BAX or MDM2.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of neurodegenerative diseases including, but not limited to,Alzheimer's disease, multiple sclerosis, Huntington's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,amyotrophic lateral sclerosis, or encephalitis.

Another embodiment of the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of viral infections and diseases including but not limited to,herpes simplex-1 or-2 viral infections, hepatitis A, hepatitis C, SARScoronavirus infection and disease, Epstein-Barr virus, rhinoviralinfections and diseases, adenoviral infections and diseases, orpoliomyelitis.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory diseases or conditions is associated withmetabolic disorders including, but not limited to, Type II diabetes,insulin resistance cardiovascular disease, arrhythmia, atherosclerosis,coronary artery disease, hypertriglyceridemia, dyslipidemia,retinopathy, nephropathy, neuropathy, or macular edema.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory diseases or conditions is associated withinflammatory bowel diseases including, but not limited to, ileitis,ulcerative colitis, Barrett's syndrome, or Crohn's disease

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of USP7 including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds or compositions of the presentinvention which inhibit USP7 is to provide treatment to patients orsubjects suffering from cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 or 400MHz. Spectra are given in ppm (δ) and coupling constants, J, arereported in Hertz. Tetramethylsilane (TMS) was used as an internalstandard. Mass spectra were collected using a Waters ZQ Single Quad MassSpectrometer (ion trap electrospray ionization (ESI)). Purity and lowresolution mass spectral data were measured using Waters Acquity i-classultra-performance liquid chromatography (UPLC) system with Acquity PhotoDiode Array Detector, Acquity Evaporative Light Scattering Detector(ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using WatersMassLynx 4.1 software and purity characterized by UV wavelength 220 nm,evaporative light scattering detection (ELSD) and electrospray positiveion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/FormicAcid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21mins. Preparatory HPLC purifications were conducted on a Waters SunFireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mm, Waters XBridge BEH C18OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mm with UV detection (Waters 2489UV/998 PDA), Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150mm, Waters XBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm, or Waters XSelect CSH C18 OBD Prep Column, 130 Å, 5 μm, 19mm×150 mm at 254 nm or 220 nm using a standard solvent gradient program(i.e., HPLC Methods 1-8 or as designated below). The absoluteconfiguration of the separated enantiomers of the compounds in theexamples described herein were not determined. As such, theconfiguration of the resolved materials were arbitrarily assigned as Ror S in each case.

Preparative HPLC Method 1 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase Bacetonitrile with 0.1% formic acidColumn: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 0% B for 0.9 min, then 0% to 5% in 0.01 min; then 5%to 35% in 3.84 min; then 35% to 100% in 0.01 min; hold at 100% for 0.74min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 2 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobilephase B acetonitrile with 0.1% ammonium hydroxideColumn: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 0% B for 0.9 min, then 0% to 5% in 0.01 min; then 5%to 35% in 3.84 min; then 35% to 100% in 0.01 min; hold at 100% for 0.74min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 3 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase Bacetonitrile with 0.1% formic acidColumn: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: 15% for 0.9 min, then 15% to 25% in 0.01 min, then 25% to65% in 3.84 min; and 65% to 100% in 0.01 min; hold at 100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 4 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobilephase B acetonitrile with 0.1% ammonium hydroxideColumn: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 15% B for 0.9 min, then 15% to 25% in 0.01 min; then25% to 65% in 3.84 min; then 65 to 100% to 100% in 0.01 min; hold at100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 5 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase Bacetonitrile with 0.1% formic acidColumn: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 35% B for 0.9 min, then 35% to 45% in 0 01 min; then45% to 85% in 3.84 min; then 85 to 100% to 100% in 0.01 min; hold at100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 6 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ MassDetector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobilephase B acetonitrile with 0.1% ammonium hydroxideColumn: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 35% B for 0.9 min, then 35% to 45% in 0.01 min; then45% to 85% in 3.84 min; then 85 to 100% to 100% in 0.01 min; hold at100% for 0.74 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 7 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% formic acid/Mobile phase Bacetonitrile with 0.1% formic acidColumn: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 50% B for 0.9 min, then 50% to 60% in 0.01 min; then60% to 100% in 3.84 min; then hold at 100% for 0.75 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+

Preparative HPLC Method 8 (ESI, 5.5 min Method):

Instruments: HPLC: Waters 2545 Binary Gradient Module. MS: Waters3100/ZQ Mass Detector. UV: Waters 2489 UV/998 PDA.Conditions: Mobile phase A: water with 0.1% ammonium hydroxide/Mobilephase B acetonitrile with 0.1% ammonium hydroxideColumn: Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×50 mmColumn temperature: AmbientLC gradient: Hold 50% B for 0.9 min, then 50% to 60% in 0.01 min; then60% to 100% in 3.84 min; then hold at 100% for 0.75 min.LC Flow rate: 23 mL/min binary pump, 2 mL/min acetonitrile at columndilutionUV wavelength: 220 nm and 254 nmIonization Mode: Electrospray Ionization; positive/negative; ESI+Abbreviations used in the following examples and elsewhere herein are:

-   -   atm atmosphere    -   br broad    -   BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)    -   DABCO 1,4-diazabicyclo[2.2.2]octane    -   DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   ESI electrospray ionization    -   h hour(s)    -   HATU        [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   MHz megahertz    -   min minutes    -   MPLC Medium pressure liquid chromatography    -   MS molecular sieves    -   MTBE 2-methoxy-2-methylpropane    -   MW microwave    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   TBDMS tertbutyldimethylsilyl    -   TFA Trifluoroacetic acid    -   TLC thin layer chromatography    -   X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 1: Intermediate 2-1. tert-Butyl4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

The title compound (16.7 g, 77%). was prepared according to theprocedure described for Example 21, Intermediate 2-29, Step 4, utilizing1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (9.0 g, 59.9 mmol) asstaring material ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.99 (s, 1H),4.24-3.98 (m, 2H), 4.00 (s, 3H), 3.97-3.78 (m, 2H), 3.21-3.09 (m, 2H),2.96 (s, 1H), 1.66-1.56 (m, 2H), 1.56-1.48 (m, 2H), 1.45 (s, 9H) ppm.LCMS: (ESI) m/z 386 [M+Na].

Example 2: Intermediate 2-2.5-((4-Hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onetrifluoroacetic acid salt

The title compound was prepared according to the procedure described forExample 21 described herein below, Intermediate 2-28, Step 5, utilizingtert-butyl4-hydroxy-4-((1-methyl-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidine-1-carboxylatefrom Intermediate 2-1 (7.80 g, 21.5 mmol) as starting material which wasused without any further purification. LCMS: (ESI) m/z 264 [M+H].

Example 2a: Intermediate 2-2a.5-((4-Hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,hydrochloric acid salt

In a ½ dram reaction vial, tert-butyl4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)piperidine-1-carboxylate(Intermediate 2-1, 0.2 M 1,4-dioxane, 0.15 mL, 0.030 mmol) andhydrochloric acid (4.0 M 1,4-dioxane, 0.075 mL, 0.3 mmol) were combined.The vial was capped and agitated at 50° C. for 3 hours. The reaction wascooled and dried under a stream of nitrogen to provide5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,hydrochloric acid salt without any further purification. LCMS: (ESI) m/z264 [M+H].

TABLE 1 The Intermediates in Table 1 were synthesized according to theprocedure described in Example 2a above. LCMS: (ESI) Intermediate No.:Precursor Used m/z [M + H] Intermediate 2-2b. 1-(4-chlorophenyl)-5-((4-Intermediate 2-28 360, 362 hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloric acid salt Intermediate 2-86.1-(4-fluorophenyl)-5-((4- Intermediate 2-29 344hydroxypiperidin-4-yl)methyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloric acid salt

Example 3: Intermediate 2-3.5-((1-(4-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

A 100-mL round-bottom flask was charged with5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onetrifluoroacetic acid salt (Intermediate 2-2, 2.70 g, 7.15 mmol),4-bromobenzoic acid (1.51 g, 7.51 mmol), and 1,2-dichloroethane (38 mL).Hydroxybenzotriazole hydrate (547 mg, 3.58 mmol), triethylamine (4.98mL, 35.8 mmol), and EDC (1.44 g, 7.51 mmol) were then added to theslurry. The reaction mixture was stirred at 50° C. for 3 h. Theresulting suspension was cooled in an ice bath and stirred for 30 min.The solids were filtered and washed with 9:1 hexanes-ethyl acetate (25mL) to afford5-((1-(4-bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-3, 2.58 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H),7.96 (s, 1H), 7.54 (d, 2H), 7.28 (d, 2H), 4.55-4.36 (m, 1H), 4.27-4.12(m, 1H), 4.09-3.93 (m, 1H), 4.00 (s, 3H), 3.69-3.51 (m, 1H), 3.50-3.34(m, 1H), 3.32 (s, 1H), 1.80-1.62 (m, 2H), 1.62-1.44 (m, 2H) ppm. LCMS:(ESI) m/z 446, 448 [M+H].

The Intermediate in Table 2 was synthesized according to the procedureoutlined in Example 3 above.

TABLE 2 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-4. 5-((1-(3-Bromobenzoyl)- 2-2 and 446, 4484-hydroxypiperidin-4-yl)methyl)-1-methyl- 3-bromo-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin- benzoic acid 4-one

Example 4: Intermediate 2-5.2′-(Cyanomethyl)-[1,1′-biphenyl]-4-carboxylic acid

2-(2-Bromophenyl)acetonitrile (500 mg, 2.55 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (633 mg,2.55 mmol), tetrakis[triphenylphosphine]palladium(0) (147 mg, 0.13mmol), tribasic potassium phosphate (1.62 g, 7.64 mmol), 1,4-dioxane (30mL) and water (3 mL) were added to a 100-mL round-bottom flask fittedwith a nitrogen inlet, magnetic stir bar and condenser. The resultingsolution was stirred for 16 h at 100° C. The solids were removed byfiltration and the filtrate was concentrated under vacuum. The residuewas purified by preparative TLC with ethyl acetate/petroleum ether (1:5v/v) to provide 2′-(cyanomethyl)-[1,1′-biphenyl]-4-carboxylic acid(Intermediate 2-5, 500 mg, 83%). LCMS: (ESI) m/z 236 [M−H].

The Intermediates in Table 3 were synthesized according to the procedureoutlined in Example 4 above.

TABLE 3 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-134 2-bromoaniline and 4-(tetramethyl-1,3,2- 2142′-aminobiphenyl-4-carboxylic acid dioxaborolan-2-yl)benzoic acid,utilizing 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloridecomplex with dichloromethane as the catalyst Intermediate 2-251-(2-Bromophenyl)cyclopropane-1- 262 (M − H)2′-(1-cyanocyclopropyl)-[1,1′- carbonitrile and4-(4,4,5,5-tetramethyl-1,3,2- biphenyl]-4-carboxylic aciddioxaborolan-2-yl)benzoic acid

Example 5: Intermediate 2-229a.4-(5-(tert-butoxycarbonyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)benzoicacid

Step 1. tert-butyl5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate

A 100-mL round-bottom flask was charged with ethyl 4-bromobenzoate (500mg, 2.18 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct(226 mg, 0.22 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (261mg, 0.44 mmol), cesium carbonate (2.14 g, 6.57 mmol), toluene (20 mL)and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (521 mg,2.61 mmol). The resulting solution was stirred for 24 h at 110° C. Thereaction was cooled to room temperature and quenched by the addition ofwater (20 mL). The resulting solution was extracted with ofdichloromethane (4×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparative thin layer chromatography elutingwith ethyl acetate/petroleum ether (1:10 to 1:1, v/v). The collectedfractions were combined and concentrated under vacuum to affordtert-butyl5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylateas a yellow oil (700 mg, 92%). LCMS: (ESI) m/z 347 [M+H].

Step 2.4-(5-(tert-butoxycarbonyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)benzoicacid (2-229a)

The title compound was prepared according to the procedure outlined inExample 10, Step 2 utilizing tert-butyl5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate(600 mg, 1.73 mmol) as starting material (370 mg, 67%). LCMS: (ESI) m/z319 [M+H].

Example 6: Intermediate 2-7.5-((4-Hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

In a 20 mL vial was added5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onetrifluoroacetic acid salt (Intermediate 2-2) (0.643 g, 1.71 mmol),4-(hydroxymethyl)benzoic acid (0.310 g, 2.04 mmol) and HATU (775 mg,2.04 mmol) in DMF (6.8 mL) followed by triethylamine (2.13 mL, 15 3mmol) to give a tan solution. The reaction was stirred for 24 h, dilutedwith ethyl acetate (50 mL) and poured into a separatory funnel. Theorganic layer was washed successively with saturated aqueous ammoniumchloride (25 mL), saturated aqueous sodium bicarbonate (25 mL), andsaturated aqueous sodium chloride (25 mL). The organic layer wasseparated, dried with anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to give a residue which was purifiedby column chromatography (Biotage, 50 g silica gel column, eluting withethyl acetate/hexanes gradient) to give5-((4-hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-c]pyrimidin-4-one(Intermediate 2-7, 300 mg, 37%). H NMR (300 MHz, DMSO-d₆) δ 8.23 (s,1H), 8.06 (s, 11H), 7.37-7.30 (m, 4H), 4.96, (s, 1H), 4.50 (s, 2H),4.2-4.0 (m, 3H), 3.89 (s, 3H), 3.5-3.2 (m, 4H), 1.7-1.2 (m, 4H) ppm.LCMS: (ESI) m/z 397.95 [M+H].

The Intermediates in Table 4 were synthesized according to the proceduredescribed for Example 6 above.

TABLE 4 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-38. 5-((1-(2′-amino-[1,1′- 2-2 and4-(2-aminophenyl)benzoic 459 biphenyl]-4-carbonyl)-4-hydroxypiperidin-acid 4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-30. 1-(4-Bromophenyl)-5-1-(4-bromophenyl)-5-((4- 472, 474 ((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-hydroxypiperidin-4-yl)methyl)-1,5-dihydro- dihydro-4H-pyrazolo[3,4-4H-pyrazolo[3,4-d]pyrimidin-4-one d]pyrimidin-4-one and cyclopropanoicacid Intermediate 2-31. 1-(3-bromophenyl)-5- 1-(3-bromophenyl)-5-((4-472, 474 ((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-hydroxypiperidin-4-yl)methyl)-1,5-dihydro- dihydro-4H-pyrazolo[3,4-4H-pyrazolo[3,4-d]pyrimidin-4-one d]pyrimidin-4-one and cyclopropanoicacid Intermediate 2-870. 5-([1-[(4- 1-(4-fluorophenyl)-5-((4- 526, 528bromophenyl)carbonyl]-4- hydroxypiperidin-4-yl)methyl)-1,5-hydroxypiperidin-4-yl]methyl)-1-(4- dihydro-4H-pyrazolo[3,4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4- d]pyrimidin-4-one and 4-d]pyrimidin-4-one bromobenzoic acid Intermediate 2-871. 3-(5-((1- I-20and cyclopropanoic acid 437 (cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1- yl)benzoic acid Intermediate2-872. 1-(4-bromophenyl)-5- 1-(4-bromophenyl)-5-((4- 487((4-hydroxy-1-(1-methylcyclopropane-1-hydroxypiperidin-4-yl)methyl)-1,5- carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oned]pyrimidin-4-one and 1- methylcyclopropane-1-carboxylic acidIntermediate 2-873. 1-(3-bromophenyl)-5- 1-(3-bromophenyl)-5-((4- 486,488 ((4-hydroxy-1-(1-methylcyclopropane-1-hydroxypiperidin-4-yl)methyl)-1,5- carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oned]pyrimidin-4-one and 1- methylcyclopropane-1-carboxylic acidIntermediate 2-874. 1-(3-bromophenyl)-5- 1-(3-bromophenyl)-5-((4- 526,528 ((1-(4-fluorobenzoyl)-4-hydroxypiperidin-hydroxypiperidin-4-yl)methyl)-1,5-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one d]pyrimidin-4-one and 4- fluorobenzoic acidIntermediate 2-875. 1-(4-bromophenyl)-5- 1-(4-bromophenyl)-5-((4- 526,528 ((1-(4-fluorobenzoyl)-4-hydroxypiperidin-hydroxypiperidin-4-yl)methyl)-1,5-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one d]pyrimidin-4-one and 4- fluorobenzoic acidIntermediate 2-876. 1-(4-bromophenyl)-5- 1-(4-bromophenyl)-5-((4- 514((4-hydroxy-1-(2-methyloxazole-5- hydroxypiperidin-4-yl)methyl)-1,5-carbonyl)piperidin-4-yl)methyl)-1,5- dihydro-4H-pyrazolo[3,4-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one d]pyrimidin-4-one and 2-methyloxazole-5-carboxylic acid Intermediate 2-844a. 1-(4-bromophenyl)-1-(4-bromophenyl)-5-((4- 538, 540 5-([1-[(2-cyclopropyl-1,3-oxazol-5-hydroxypiperidin-4-yl)methyl)-1,5- yl)carbonyl]-4-hydroxypiperidin-4-dihydro-4H-pyrazolo[3,4- yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one and 2- d]pyrimidin-4-onecyclopropyloxazole-5-carboxylic acid Intermediate 2-859a: 5-((1-(4-5-((4-hydroxypiperidin-4- 494 fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4- yl)methyl)-1-(4-(methylthio)phenyl)-1H-(methylthio)phenyl)-1,5-dihydro- pyrazolo[3,4-d]pyrimidin-4(5H)-one4H-pyrazolo[3,4-d]pyrimidin-4-one and 4-fluorobenzoic acid Intermediate2-320a: 4-(2-chloro-5-[5-[(1- 1-(3-bromo-4-chlorophenyl)-5-((4- 554cyclopropanecarbonyl-4-hydroxypiperidin-hydroxypiperidin-4-yl)methyl)-1,5- 4-yl) methyl]-4-oxo-1H,4H,5H-dihydro-4H-pyrazolo[3,4- pyrazolo[3,4-d]pyrimidin-1- d]pyrimidin-4-oneand yl]phenyl)piperazine-1-carboxylate cyclopropanoic acid Intermediate2-31. 1-(4-bromophenyl)-5- 1-(4-bromophenyl)-5-((4- 522, 524([4-hydroxy-1-[(4- hydroxypiperidin-4-yl)methyl)-1,5-methylphenyl)carbonyl]piperidin-4- dihydro-4H-pyrazolo[3,4-yl]methyl)-1H,4H,5H-pyrazolo[3,4- d]pyrimidin-4-one and 4-d]pyrimidin-4-one methylbenzoic acid Intermediate 2-31a. 5-((1-5-((4-hydroxypiperidin-4- 424 (cyclopropanecarbonyl)-4-yl)methyl)-1-(4-methoxyphenyl)- hydroxypiperidin-4-yl)methyl)-1-(4-1,5-dihydro-4H-pyrazolo[3,4- methoxyphenyl)-1,5-dihydro-4H-d]pyrimidin-4-one and pyrazolo[3,4-d]pyrimidin-4-one cyclopropanoic acidIntermediate 2-31b. 1-(3-bromo-4- 1-(3-bromo-4-fluorophenyl)-5-((4- 490,492 fluorophenyl)-5-((1- hydroxypiperidin-4-yl)methyl)-1,5-(cyclopropanecarbonyl)-4- dihydro-4H-pyrazolo[3,4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro- d]pyrimidin-4-one, TFA saltand 4H-pyrazolo[3,4-d]pyrimidin-4-one cyclopropanoic acid

Example 7: Intermediate 2-7b. 1-(5-bromopyridin-2-yl)pyrrolidin-3-ol

A 250-mL round-bottom flask fitted with a nitrogen balloon, magneticstir bar, condenser and thermometer was charged with pyrrolidin-3-ol(350 mg, 4.02 mmol), 5-bromo-2-iodopyridine (1 g, 3.52 mmol), toluene(60 mL), tris(dibenzylideneacetone)dipalladium (80 mg, 0.09 mmol),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg, 0.18 mmol)and sodium tert-butoxide (1.02 g, 10.6 mmol). The reaction mixture wasstirred for 14 h at 70° C. in an oil bath. After cooling to 23° C., thereaction was quenched with water (60 mL). The product was extracted withethyl acetate (4×60 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography eluting withdichloromethane/methanol (10:1 v/v) to afford1-(5-bromopyridin-2-yl)pyrrolidin-3-ol as a red solid (300 mg, 35%).LCMS: (ES) m/z 243, 245 [M+H].

Example 8: Intermediate 2-8.2-Phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

Step 1. Methyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylatehydrochloride (230 mg, 1.01 mmol), bromobenzene (230 mg, 1.47 mmol), andcesium carbonate (0.66 g, 2.02 mmol) in 1,4-dioxane (10 mL) was purgedwith nitrogen. RuPhos precatalyst (15 mg, 0.020 mmol) was added and thereaction mixture was heated at 80° C. for 30 min, then 120° C. for 16 h.The solvent was removed under vacuum. The residue was diluted with water(30 mL), poured into a separatory funnel, and washed with ethyl acetate(3×50 mL). The combined organic layers were dried over sodium sulfateand the solvent was removed under vacuum and the crude mixture waspurified on silica gel using a gradient of 0-100% ethyl acetate/hexanes,to give methyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate(200 mg, 74%). ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.76 (m, 2H), 7.30-7.12(m, 3H), 6.75 (d, 2H), 6.75 (t, 1H), 4.35 (s, 2H), 3.84 (s, 3H), 3.39(t, 2H), 2.94 (t, 2H) ppm. LCMS: (ESI) m/z 268 [M+H].

Step 2. 2-Phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

Sodium hydroxide (1.0 M aqueous, 2.24 mL, 2.24 mmol) was stirred withmethyl 2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Step 1,200 mg, 0.75 mmol) in tetrahydrofuran (5 mL) at 50° C. for 48 h.Hydrochloric acid (1.0 M solution in water) was added to the reactionuntil the pH was 4. The mixture was poured into a separatory funnel andwashed with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate to afford2-phenyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (Intermediate2-8, 150 mg, 79%), which was used without any further purification.LCMS: (ESI) m/z 254 [M+H]

The Intermediates in Table 5 were synthesized according to the proceduredescribed in Example 8.

TABLE 5 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-63. 3-fluoro-4-(4- Methyl 4-bromo-3-fluorobenzoate 239methylpiperazin-1-yl)benzoic acid and 1-methylpiperazine Intermediate2-868a. 4-(5-(Tert- Methyl 4-bromo-3-benzoate and 319butoxycarbonyl)-2,5-diaza- tert-butyl 2,5-bicyclo[2.2.1]heptan-2-yl)benzoic acid diazabicyclo[2.2.1]heptane-2-carboxylate

Example 9: Intermediate 2-65.4-(8-Methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoic acid

Step 1.Ethyl-4-(3,8-diaza-bicyclo[3.2.1]octan-8-carboxylicacid,1,1-dimethylethylester-3-yl)benzoate

Title compound (300 mg, 38%) was prepared according to proceduredescribed in Example 8, Step 1, utilizing 4-bromobenzoate (500 mg, 2.18mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (930mg, 4.38 mmol) as starting materials. LCMS: (ESI) m/z 361 [M+H].

Step 2. Ethyl 4-(3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoatehydrochloride

Title compound was prepared according to the procedure outlined inExample 2a, utilizingethyl-4-(3,8-diaza-bicyclo[3.2.1]octan-8-carboxylicacid,1,1-dimethylethylester-3-yl)benzoate(Step 1, 300 mg, 0 83 mmol) as starting material which was used directlyfor next step without further purification (200 mg, 92%). LCMS: (ESI)m/z 261 [M+H].

Step 3. Ethyl 4-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate

A 100-mL round-bottom flask was charged with ethyl4-(3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate hydrochloride (Step 2,200 mg, 0.67 mmol), methanol (10 mL), formaldehyde (10 mL) and sodiumtriacetoxyborohydride (450 mg, 2.12 mmol). The resulting mixture wasstirred for 4 h at 23° C. The reaction was then quenched by the additionof water (30 mL). The resulting solution was extracted with ethylacetate (3×40 mL) and washed with brine (40 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:5 v/v) to afford to afford ethyl4-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate as a colorlessoil (170 mg, 92%). LCMS (ESI) m/z 275 [M+H].

Step 4. 4-(8-Methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoic acid

The title compound was prepared according to the procedure outlined inExample 10, Step 2 utilizing ethyl4-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)benzoate (Step 3, 170 mg,0.62 mmol) as starting material (130 mg, 85%) as a colorless oil whichwas used directly in the next step without further purification. LCMS:(ES) m/z 247 [M+H].

Example 10: Intermediate 2-9. 4-(1-Hydroxycyclopropyl)benzoic acid

Step 1. Methyl 4-(1-hydroxycyclopropyl)benzoate

Ether (30 mL), titanium(IV) isopropoxide (0.5 mL, 1.69 mmol) anddimethyl terephthalate (1.00 g, 5.15 mmol) were added to a 100-mL3-necked round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and condenser. This was followed by the addition of ethylmagnesiumbromide (3.0 M in ether, 2.6 mL, 7.80 mmol) dropwise with stirring at10° C. The resulting solution was stirred for 2 h at room temperatureand then quenched by the addition of sulfuric acid (15% wt, 50 mL). Theresulting solution was extracted with ethyl acetate (4×30 mL). Theorganic layers were combined and washed with saturated aqueous sodiumcarbonate (50 mL) and brine (50 mL). The mixture was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparative TLC plate with petroleum ether/ethylacetate (15:1 v/v) to afford methyl 4-(1-hydroxycyclopropyl)benzoate(250 mg, 25%). LCMS: (ESI) m/z 193 [M+H].

Step 2. 4-(1-Hydroxycyclopropyl)benzoic acid

Methanol (20 mL), methyl 4-(1-hydroxycyclopropyl)benzoate (Step 1, 200mg, 1.04 mmol), and lithium hydroxide (10% aqueous, 5 mL) were added toa 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and condenser. The resulting solution was stirred for 1 h at roomtemperature. The pH value of the solution was adjusted to 4 withhydrogen chloride (1.0 M aqueous). The resulting solution was extractedwith dichloromethane (4×20 mL) and the organic layers were combined,dried over anhydrous sodium sulfate and concentrated under vacuum toafford 4-(1-hydroxycyclopropyl)benzoic acid (Intermediate 2-9) which wasused without further purification. LCMS: (ESI) m/z 177 [M−H].

Example 11: Intermediate 2-11.5-((4-Hydroxypiperidin-4-yl)methyl)-1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt

Step 1. 2-Bromo-5-hydrazinylpyridine

Title compound (500 mg, 23%) was prepared according to proceduredescribed in procedure used for intermediate 2-28a, utilizing6-Bromopyridin-3-amine (2.00 g, 11.6 mmol) as starting material whichwas purified by column chromatography eluting withdichloromethane/methanol (20:1 v/v). LCMS: (ESI) m/z 188, 190 [M+H].

Step 2. 5-Amino-1-(6-bromopyridin-3-yl)-1H-pyrazole-4-carbonitrile

Title compound (235 mg, 33%) was prepared according to procedureoutlined in Example 21, Step 1 utilizing2-(ethoxymethylidene)propanedinitrile (326 mg, 2.67 mmol) and2-bromo-5-hydrazinylpyridine (Step 1, 500 mg, 2.66 mmol) as startingmaterials LCMS: (ESI) m/z 264, 266 [M+H].

Step 3. 5-Amino-1-(6-phenylpyridin-3-yl)-1H-pyrazole-4-carbonitrileBuchwald dppf, phosphate tribasic

Title compound (180 mg, 93%) was prepared according to procedureoutlined in Example 5 utilizing5-Amino-1-(6-bromopyridin-3-yl)-1H-pyrazole-4-carbonitrile (Step 2, 195mg, 0.74 mmol), phenylboronic acid (136 mg, 1.11 mmol), 1,4-dioxane (15mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (48 mg) followed by column chromatographypurification using ethyl acetate/petroleum ether (1:1 v/v) LCMS: (ESI)m/z 262 [M+H].

Step 4.1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

5-Amino-1-(6-phenylpyridin-3-yl)-1H-pyrazole-4-carbonitrile (Step 3, 170mg, 0.65 mmol, 1.00 equiv) and formic acid (18 mL) were added to a100-mL round-bottom flask fitted with a magnetic stir bar and condenser.The resulting solution was heated at reflux for 16 h, then cooled toroom temperature and concentrated under vacuum. The solids were washedwith ethyl acetate (3×20 mL) and dried to give1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(170 mg, 90%). LCMS: (ESI) m/z 290 [M+H].

Step 5. tert-Butyl4-hydroxy-4-((4-oxo-1-(6-phenylpyridin-3-yl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

Title compound (235 mg, 33%) was prepared according to procedureoutlined in Example 21, Step 4 utilizing1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Step 4, 160 mg, 0.55 mmol) as starting material followed by columnchromatography purification using ethyl acetate/petroleum ether (1:3v/v) (210 mg, 76%). LCMS: (ESI) m/z 503 [M+H].

Step 6.5-((4-Hydroxypiperidin-4-yl)methyl)-1-(6-phenylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt

Title compound (235 mg, 33%) was prepared according to procedureoutlined in Example 21, Step 5 utilizing tert-Butyl4-hydroxy-4-((4-oxo-1-(6-phenylpyridin-3-yl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Step 5, 210 mg,0.42 mmol), as starting material which was used without furtherpurification. LCMS: (ESI) m/z 402 [M+H].

The Intermediates in Table 6 were synthesized according to the proceduredescribed for Example 11, Steps 2, 3 and Step 6.

TABLE 6 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-32. 5-[(4-hydroxypiperidin-1-(4-Bromophenyl)-1,5-dihydro- 402 4-yl)methyl]-1-(4-phenylphenyl)-1H,4H, 4H-pyrazolo[3,4-d]pyrimidin-4-one5H-pyrazolo [3,4-d] pyrimidin-4-one, and phenylboronic acidtrifluoroacetic acid salt Intermediate 2-877. 1-(4′-fluoro-[1,1′-1-(4-Bromophenyl)-1,5-dihydro- 420biphenyl]-4-yl)-5-((4-hydroxypiperidin-4-4H-pyrazolo[3,4-d]pyrimidin-4-oneyl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- and 4-fluorophenylboronic acidd]pyrimidin-4-one, trifluoroacetic acid salt Intermediate 2-879. 5-((4-1-(4-Bromophenyl)-1,5-dihydro- 470 hydroxypiperidin-4-yl)methyl)-1-(3′-4H-pyrazolo[3,4-d]pyrimidin-4-one (trifluoromethyl)biphenyl-4-yl)-1H-and 3-trifluorophenylboronic acid pyrazolo[3,4-d]pyrimidin-4 (5H)-one,trifluoroacetic acid salt

Example 12: Intermediate 2-13. 2-Chloro-4-phenoxybenzoic acid

2-Chloro-4-hydroxybenzoic acid (3.00 g, 17.4 mmol), dichloromethane (100mL), phenylboronic acid (4.24 g, 34.8 mmol), copper (II) acetate (7.87g, 43.3 mmol), triethylamine (5.27 g, 52.1 mmol) and 4 Å molecularsieves (MS) (3.00 g) were added to a 250-mL round-bottom flask fittedwith a nitrogen inlet and magnetic stir bar. The reaction mixture wasstirred for 16 h at room temperature. The solids were filtered and thefiltrate was concentrated under vacuum. The residue was purified on asilica gel column with dichloromethane/methanol (10:1 v/v) to afford2-chloro-4-phenoxybenzoic acid (Intermediate 2-13, 790 mg, 18%). LCMS:(ESI) m/z 247 [M−H].

Example 13: Intermediate 2-26. 2-Phenyloxazole-5-carboxylic acid

Step 1. Methyl 2-phenyloxazole-5-carboxylate

5-Bromo-2-phenyl-1,3-oxazole (500 mg, 2.23 mmol),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II), complexwith dichloromethane (96 mg, 0.12 mmol), triethylamine (1.00 mL, 7.17mmol) and methanol (20 mL) were added to a 50-mL pressure tank reactor(3 atm) fitted with a magnetic stir bar and thermometer. The reactor wasevacuated and flushed three times with nitrogen. Carbon monoxide wasbubbled into the reactor and the resulting mixture was stirred for 16 hat 120° C. The reaction was then quenched by the addition water (50 mL)and extracted with dichloromethane (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (1:2 v/v) toafford methyl 2-phenyloxazole-5-carboxylate (350 mg, 77%). LCMS: (ESI)m/z 204 [M+H].

Step 2. 2-Phenyloxazole-5-carboxylic acid

Title compound was prepared according to procedure outlined in Example10, Step 2, utilizing methyl 2-phenyloxazole-5-carboxylate (Step 1, 350mg, 1.72 mmol) as starting material, and was used without furtherpurification. LCMS: (ESI) m/z 188 [M−H].

Example 14: Intermediate 2-17. 1-Benzyl-1H-pyrrole-2-carboxylic acid

Ethyl 1-benzyl-1H-pyrrole-2-carboxylate (458 mg, 2.00 mmol), potassiumhydroxide (1.12 g, 20.0 mmol), water (10 mL) and methanol (50 mL) wereadded to a 100-mL round-bottom flask fitted with a magnetic stir bar,thermometer and condenser. The resulting solution was stirred for 16 hat 70° C. The pH of the solution was adjusted to 2 with hydrochloricacid (6.0 M aqueous) and the resulting solution was extracted with ethylacetate (3×30 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum to give1-benzyl-1H-pyrrole-2-carboxylic acid (Intermediate 2-17), which wasused in the next step without purification. LCMS: (ESI) m/z 200 [M−H]

Example 15: Intermediate 2-21. 3-(1H-Pyrazol-1-yl)butanoic acid

Step 1. Ethyl 3-(1H-pyrazol-1-yl)butanoate

1H-pyrazole (1.00 g, 14.7 mmol), ethyl (E)-but-2-enoate (2.50 g, 21.9mmol), acetonitrile (30 mL) and DBU (1.20 g, 7.88 mmol) were added to a100-mL round-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 16 h at room temperature. The reaction was thenquenched by the addition of water (50 mL) and extracted withdichloromethane (3×40 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum to giveethyl 3-(1H-pyrazol-1-yl)butanoate which was used in the next stepwithout any further purification. LCMS: (ESI) m/z 183 [M+H].

Step 2. 3-(1H-Pyrazol-1-yl)butanoic acid

Title compound was prepared according to a similar procedure outlinedfor Example 10, Step 2 utilizing ethyl 3-(1H-pyrazol-1-yl)butanoate(Step 1, 2.0 g, 11.0 mmol) as starting material which was used withoutfurther purification.

Example 16: Intermediate 2-51. 4,4-difluoro-3-(1H-pyrazol-1-yl)butanoicacid

Step 1. Ethyl 4,4-difluoro-3-oxobutanoate

A 500-mL round-bottom flask was charged with sodium ethoxide (28.3 g,416 mmol) and ethanol (80 mL) followed by the addition of a solution ofethyl 2,2-difluoroacetate (43 g, 347 mmol) in ethyl acetate (170 mL)added slowly with stirring at 23° C. The resulting solution was stirredfor 2 h at 60° C. Upon cooling to 23° C., the reaction was quenched bythe addition of hydrochloric acid (6M, 150 mL) and the pH of thesolution was adjusted to 4-5. The resulting solution was extracted withethyl acetate (3×200 mL) and the organic layers were combined and driedover anhydrous sodium sulfate and concentrated under vacuum to affordethyl 4,4-difluoro-3-oxobutanoate as a colorless oil which was usedwithout further purification (29 g, 42%). GCMS m/z 166.

Step 2. Ethyl 4,4-difluoro-3-hydroxybutanoate

A 500-mL round-bottom flask was charged with ethyl4,4-difluoro-3-oxobutanoate (8 g, 48.16 mmol), toluene (250 mL) andsodium borohydride (2.38 g, 64.63 mmol). The resulting solution wasstirred for 2 h at 65° C. The reaction was then quenched by the additionof water (100 mL) The resulting solution was extracted with ethylacetate (3×50 mL) and the organic layers were combined, washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:5 to 1:2 v/v) to afford ethyl4,4-difluoro-3-hydroxybutanoate (6.81 g, 84%). GCMS m/z 168.

Step 3. (E)-ethyl 4,4-difluorobut-2-enoate

A 25-mL round-bottom flask was charged with ethyl4,4-difluoro-3-hydroxybutanoate (5 g, 48.16 mmol) and phosphoruspentoxide (3.4 g, 23.62 mmol). The resulting solution was stirred for 2h at 70° C. in an oil bath. The crude product was purified bydistillation under reduced pressure (1 mm Hg) and the fraction wascollected at 100° C. to give (E)-ethyl 4,4-difluorobut-2-enoate as acolorless oil (1.8 g, 25%). GCMS m/z 150.

Step 4. 4,4-difluoro-3-(1H-pyrazol-1-yl)butanoic acid

A 100-mL round-bottom flask was charged with 1H-pyrazole (102 mg, 1.50mmol) and tetrahydrofuran (20 mL) followed by the addition of sodiumhydride (52 mg, 2.17 mmol) at 0° C. The resulting solution was stirred30 min at 0° C. before adding (E)-ethyl 4,4-difluorobut-2-enoate (150mg, 1.00 mmol). The resulting solution was stirred 16 h at 23° C. Thereaction was quenched by the addition of 10 mL of water and extractedwith ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to4-5 with hydrochloride (6 M) and extracted with dichloromethane (2×30mL). The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated under vacuum to give4,4-difluoro-3-(1H-pyrazol-1-yl)butanoic acid (90 mg) as a yellow oilwhich was used without further purification. LCMS: (ESI) r/z 191 [M+H].

The Intermediates below were synthesized according to the proceduresoutlined in Example 16 above.

TABLE 7 MS (ESI, Intermediate No.: Precursor Used m/z) [M + H]Intermediate 2-52. 4,4-difluoro-3-(5-fluoro-1H- 3-fluoro-1H-pyrazole 209pyrazol-1-yl)butanoic acid Intermediate 2-53.4,4-difluoro-3-(4-fluoro-1H- 4-fluoro-1H-pyrazole 209pyrazol-1-yl)butanoic acid Intermediate 2-99.3-(4-chloro-1H-pyrazol-1-yl)- 4-chloro-1H-pyrazole 225, 2274,4-difluorobutanoic acid Intermediate 2-100. 3-(3-chloro-1H-pyrazol-1-3-chloro-1H-pyrazole 225, 227 yl)-4,4-difluorobutanoic acid Intermediate2-101. 4,4-difluoro-3-(4-methyl- 3-methyl-1H-pyrazole 2051H-pyrazol-1-yl)butanoic acid Intermediate 2-98. 3- ethyl 3-oxobutanoate(Step 173 (difluoromethoxy)cyclobutanecarboxylic acid 2) and3-fluoro-1H-pyrazole Intermediate 2-163. 4,4,4-Trifluoro-3-(1H-2,2,2-trifluoroacetate (Step 209 pyrazol-1-yl)butanoic acid 1) and1H-pyrazole Intermediate 2-163A. 4,4,4-trifluoro-3-(3-fluoro-2,2,2-trifluoroacetate (Step 227 1H-pyrazol-1-yl)butanoic acid 1) and3-fluoro-1H-pyrazole

Example 17: Intermediate 2-43. 4-Fluoro-3-phenylbutanoic acid

Step 1. Ethyl (Z)-4-fluoro-3-phenylbut-2-enoate

Sodium hydride (188 mg, 7.83 mmol) and tetrahydrofuran (10 mL) wereadded to a 3-necked 100-mL round-bottom flask fitted with a nitrogeninlet, magnetic stir bar, and thermometer. Ethyl2-(diethoxyphosphoryl)acetate (1.05 g, 4.68 mmol) was added dropwisewith stirring at 0° C. and the resulting solution was stirred for 1 h at0° C. A solution of 2-fluoro-1-phenylethan-1-one (500 mg, 3.62 mmol) intetrahydrofuran (10 mL) was added at 0° C. and the resulting solutionwas stirred for 30 min at 0° C. and then for 16 h at room temperature.The reaction was quenched by the addition of saturated aqueous ammoniumchloride (30 mL) and extracted with ether (4×30 mL). The organic layerswere combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography using ethyl acetate/petroleum ether (1:30 v/v) to affordethyl (Z)-4-fluoro-3-phenylbut-2-enoate (630 mg, 84%). LCMS: (ESI) m/z209 [M+H].

Step 2. Ethyl 4-fluoro-3-phenylbutanoate

Ethyl (Z)-4-fluoro-3-phenylbut-2-enoate (Step 1, 200 mg, 0.96 mmol),palladium on carbon (10% wt, 30 mg) and ethyl acetate (30 mL) were addedto a 100-mL round-bottom flask fitted with a magnetic stir bar. Thereaction mixture was purged and pressurized with hydrogen (2 atm) andthen stirred for 40 min at room temperature. The reaction mixture wasthen filtered and concentrated under reduced pressure to afford ethyl4-fluoro-3-phenylbutanoate which was used in next step without furtherpurification. GCMS: m/z 210 [M+].

Step 3. 4-Fluoro-3-phenylbutanoic acid

Ethyl 4-fluoro-3-phenylbutanoate (200 mg, 0.96 mmol), lithium hydroxide(202 mg, 4.80 mmol), water (5 mL) and methanol (20 mL) were added to a100-mL round-bottom flask fitted with a magnetic stir bar. The resultingsolution was stirred for 2 h at room temperature. The pH was adjusted to5 with hydrogen chloride (6.0 M aqueous) and the mixture was extractedwith dichloromethane (5×20 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The crude product was purified by preparative HPLC (Waters SunFire C18OBD Prep Column, 100 Å, 5 μm, 19 mm×150 mm; Mobile phase A: 0.05%aqueous trifluoroacetic acid, Mobile phase B: acetonitrile; Gradient:20% B to 60% B over 12 min; Detector: 220 and 254 nm) to give4-fluoro-3-phenylbutanoic acid (Intermediate 2-43, 89 mg, 51%). LCMS:(ESI) m/z 181 [M−H]. ¹H NMR (300 MHz, CDCl₃) δ 10.29-8.78 (m, 1H),7.36-6.99 (m, 5H), 4.69-4.38 (m, 2H), 3.58-3.43 (m, 1H), 2.98-2.70 (m,2H) ppm.

The Intermediates below were synthesized according to the proceduresoutlined in Example 17.

TABLE 8 MS (ESI, Intermediate No.: Precursor Used m/z)[M − H]Intermediate 2-12. 3- 1-(1,3-thiazol-2- 170 (Thiazol-2-yl)butanoic acidyl)ethan-1-one

Example 18: Intermediate 2-22. 3-(1H-Pyrrol-1-yl)butanoic acid

1H-Pyrrole (1.00 g, 14.9 mmol), ethyl (2E)-but-2-enoate (1.70 g, 14.9mmol) and DMF (20 mL) were added to a 100-mL round-bottom flask fittedwith a nitrogen inlet, magnetic stir bar and thermometer. This wasfollowed by the addition of sodium hydride (60% in mineral oil, 180 mg,4.50 mmol) at −10° C. The resulting solution was allowed to warm to roomtemperature and stirred for 16 h. The reaction was then quenched by theaddition of water (20 mL). The resulting solution was stirred for 2 h atroom temperature. The pH was adjusted to ˜6 with hydrochloric acid (1.0M aqueous). The resulting solution was extracted with dichloromethane(4×50 mL) and the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to give3-(1H-pyrrol-1-yl)butanoic acid (Intermediate 2-22) which was usedwithout further purification. LCMS: (ESI) m/z 152 [M−H]

The Intermediates below were synthesized according to the proceduresdescribed in Example 18. For 2-54 and 2-55, hydrolysis was facilitatedby the addition of a solution of lithium hydroxide (2.5 mmol) in water(20 mL).

TABLE 9 MS (ESI, Intermediate No.: Precursor Used m/z) [M + H]Intermediate 2-54. 3- octahydro- 198 (hexahydro- cyclopenta[c]pyrrolecyclopenta[c]pyrrol- 2-(1H)-yl)butanoic acid Intermediate 2-55. 3-(5,6-2,4,5,6- 195 dihydro- tetrahydro- cyclopenta[c]pyrazol-cyclopenta[c]pyrazole 2(4H)-yl)butanoic acid

Example 19: Intermediate 2-931a.1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

Step 1. Tert-butyl4-hydroxy-4-([1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate

A 100-mL round-bottom flask fitted with a nitrogen balloon, magneticstir bar, condenser and thermometer was charged with tert-butyl4-[[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate(900 mg, 1.78 mmol), 3-methylpyrrolidin-3-ol hydrochloride (990 mg, 7.19mmol), cesium carbonate (3.82 g, 11.7 mmol), 1,4-dioxane (30 mL),tetra(dibenzylideneacetone)dipalladium (207 mg, 0.18 mmol) and Xphos(171 mg, 0.36 mmol). The resulting solution was stirred for 16 h at 100°C. After cooling to 23° C., the reaction was quenched by the addition ofwater (30 mL). The resulting mixture was extracted with dichloromethane(4×30 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with dichloromethane/methanol(50:1-20:1, v/v) to give tert-butyl4-hydroxy-4-([1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H, 5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate asa yellow solid (700 mg, 75%). LCMS: (ES) m/z 525 [M+H].

Step 2.1-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

The title compound was prepared according to procedure outlined inExample 2 utilizing tert-butyl4-hydroxy-4-([I-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate (200mg, 0.38 mmol) as starting material (210 mg, >95%). LCMS: (ES) m/z 425[M+H].

Table 10: The Intermediates below were synthesized according to theprocedures described in Example 19.

TABLE 10 MS (ESI, Intermediate No.: Precursor Used m/z) [M + H]Intermediate 2-410. 1-(3-(3- tert-butyl 4-[[1-(3-bromophenyl)-4- 407,408 azabicyclo[3.1.0]hexan-3-yl)phenyl)-5-((4-oxo-1H,4H,5H-pyrazolo[3,4- hydroxypiperidin-4-yl)methyl)-1,5-d]pyrimidin-5-yl]methyl]-4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-hydroxypiperidine-1-carboxylate one and 3-azabicyclo[3.1.0]hexaneIntermediate 2-1100. 5-((4- tert-butyl 4-[[1-(3-bromophenyl)-4- 411hydroxypiperidin-4-yl)methyl)-1-(3- oxo-1H,4H,5H-pyrazolo[3,4-morpholinophenyl)-1,5-dihydro-4H- d]pyrimidin-5-yl]methyl]-4-pyrazolo[3,4-d]pyrimidin-4-one, TFA salt hydroxypiperidine-1-carboxylateand morpholine Intermediate 2-1111. 5-((4- tert-butyl4-[[1-(3-bromophenyl)-4- 424 hydroxypiperidin-4-yl)methyl)-1-(3-(4-oxo-1H,4H,5H-pyrazolo[3,4- methylpiperazin-1-yl)phenyl)-1,5-dihydro-d]pyrimidin-5-yl]methyl]-4- 4H-pyrazolo[3,4-d]pyrimidin-4-one, TFAhydroxypiperidine-1-carboxylate salt and 1-methylpiperazine Intermediate2-1112. 5-((4- tert-butyl 4-((1-(4-bromophenyl)-4- 424hydroxypiperidin-4-yl)methyl)-1-(4-(4- oxo-1,4-dihydro-5H-pyrazolo[3,4-methylpiperazin-1-yl)phenyl)-1,5-dihydro- d]pyrimidin-5-yl)methyl)-4-4H-pyrazolo[3,4-d]pyrimidin-4-one, TFA hydroxypiperidine-1-carboxylatesalt and 1-methylpiperazine Intermediate 2-1113. 5-((4- tert-butyl4-((1-(4-bromophenyl)-4- 411 hydroxypiperidin-4-yl)methyl)-1-(4-oxo-1,4-dihydro-5H-pyrazolo[3,4- morpholinophenyl)-1,5-dihydro-4H-d]pyrimidin-5-yl)methyl)-4- pyrazolo[3,4-d]pyrimidin-4-one, TFA salthydroxypiperidine-1-carboxylate and morpholine Intermediate 2-1114.5-((4- tert-butyl 4-((1-(4-bromophenyl)-4- 409hydroxypiperidin-4-yl)methyl)-1-(4- oxo-1,4-dihydro-5H-pyrazolo[3,4-(piperidin-1-yl)phenyl)-1,5-dihydro-4H- d]pyrimidin-5-yl)methyl)-4-pyrazolo[3,4-d]pyrimidin-4-one, TFA salt hydroxypiperidine-1-carboxylateand piperidine Intermediate 2-1115. 1-(4-(3- tert-butyl4-((1-(4-bromophenyl)-4- 407 azabicyclo[3.1.0]hexan-3-yl)phenyl)-5-((4-oxo-1,4-dihydro-5H-pyrazolo[3,4- hydroxypiperidin-4-yl)methyl)-1,5-d]pyrimidin-5-yl)methyl)-4- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-hydroxypiperidine-1-carboxylate 3- one, TFA salt azabicyclo[3.1.0]hexane

Example 20:N-[(2R)-2-benzyl-3-[4-hydroxy-4-({4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)piperidin-1-yl]-3-oxopropyl]prop-2-ynamide

Step 1.Tert-butyl-N-[(2S)-2-benzyl-3-[4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidin-1-yl]-3-oxopropyl]carbamate

The title compound was prepared according to the procedure outlined inExample 3 utilizing5-[(4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneTFA salt (0.20 g, 0.46 mmol) and(2R)-2-benzyl-3-[[(tert-butoxy)carbonyl]amino]propanoic acid as startingmaterials followed by column chromatography purification eluting withethyl acetate/petroleum ether (1:1 v/v) (0.190 g, 57%) LCMS: (ESI) m/z587 [M+H].

Step 2.5-([1-[(2S)-3-amino-2-benzylpropanoyl]-4-hydroxypiperidin-4-yl]methyl)-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

The title compound was prepared according to the procedure outlined inExample 2 utilizing tert-butylN-[(2S)-2-benzyl-3-[4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidin-1-yl]-3-oxopropyl]carbamate(0.190 g, 0.32 mmol) as starting material which was used without furtherpurification. LCMS: (ESI) nm/z 487 [M+H].

TABLE 11 The Intermediates below were synthesized according to theprocedures outlined in Example 20. MS (ESI, Intermediate No.: PrecursorUsed m/z) [M + H] Intermediate 2-487.5-[(4-hydroxypiperidin-4-yl)methyl]- 473(R)-5-((1-(2-amino-3-phenylpropanoyl)-4- 1-phenyl-1H,4H,5H-pyrazolo[3,4-hydroxypiperidin-4-yl)methyl)-1-phenyl- d]pyrimidin-4-one TFA salt and(R)- 1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one,2-(tert-butoxycarbonylamino)-3- TFA salt phenylpropanoic acidIntermediate 2-934a. (R)-5-((1-(azetidine- 1-(4-fluorophenyl)-5-[(4- 4272-carbonyl)-4-hydroxypiperidin-4-yl) hydroxypiperidin-4-yl)methyl]-methyl)-1-(4-fluorophenyl)-1H- 1H,4H,5H-pyrazolo[3,4-d]pyrimidin-pyrazolo[3,4-d]pyrimidin-4(5H)-one, TFA 4-one TFA salt (Intermediate2-28) salt and 1-tert-butyl-2-oxo-1-[3],3- oxazocane-7-carboxylic acidIntermediate 2-935a. 1-(4-fluorophenyl)- 1-(4-fluorophenyl)-5-[(4- 4555-((4-hydroxy-1-(piperidine-3- hydroxypiperidin-4-yl)methyl]-carbonyl)piperidin-4-yl)methyl)-1,5- 1H,4H,5H-pyrazolo[3,4-d]pyrimidin-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 4-one TFA salt (Intermediate2-28) TFA salt and 1-(tert-butoxycarbonyl)piperidine- 3-carboxylic acidIntermediate 2-111. 1-(4-fluorophenyl)-5- 1-(4-fluorophenyl)-5-[(4- 469[(4-hydroxy-1-[[(1r,4r)-4-amino- hydroxypiperidin-4-yl)methyl]-cyclohexyl]carbonyl]piperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 4-one TFA salt (Intermediate2-28) TFA salt and trans-4-[(tert- butoxy)carbonyl]aminocyclohexane-1-carboxylic acid

Example 21: Intermediates 2-28 and 2-29

1-(4-Fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-28) and tert-Butyl4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl-4-hydroxypiperidine-1-carboxylate (Intermediate 2-29)

Step 1. 5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile

2-(Methoxymethylene)malononitrile (1.00 g, 8.19 mmol), (4-fluorophenyl)hydrazine hydrochloride (1.40 g, 8.61 mmol), triethylamine (1.66 g, 16.4mmol) and ethanol (50 mL) were added to a 100-mL round-bottom flaskfitted with a magnetic stir bar and condenser. The resulting solutionwas heated at reflux for 16 h. The resulting mixture was concentratedunder vacuum. The residue was purified by column chromatography elutingwith dichloromethane/methanol (10:1 v/v) to give5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (1.00 g, 60%).LCMS: (ESI) m/z 203 [M+H].

Step 2. 5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide

5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Step 1, 900 mg,4.45 mmol) was added dropwise to sulfuric acid (10 mL) at 0° C. Theresulting solution was stirred for 2 h at 25° C. The pH of the solutionwas adjusted to 8 by the addition of sodium carbonate (10% aqueous). Theresulting mixture was extracted with dichloromethane (4×50 mL) and theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide which was used inStep 3 without further purification. LCMS: (ESI) m/z 221 [M+H].

Step 3. 1-(4-Fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Step 2, 1.00 g,4.54 mmol), triethyl orthoformate (20 mL) and acetic anhydride (20 mL)were added to a 100-mL round-bottom flask fitted with a magnetic stirbar and condenser. The resulting solution was heated at reflux for 1 hand then concentrated under vacuum. The solids were collected and washedwith hexane (3×20 mL) to afford1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one whichwas used in the next step without further purification. LCMS: (ESI) m/z231 [M+H].

Step 4. tert-Butyl4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate

1-(4-Fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Step3, 1.00 g, 4.34 mmol), tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (926 mg, 4.34 mmol), cesiumcarbonate (4.30 g, 13.2 mmol) and DMF (50 mL) were added to a 100-mLround-bottom flask fitted with a magnetic stir bar and thermometer. Theresulting solution was stirred for 5 h at 80° C. The resulting solutionwas diluted with water (50 mL). The mixture was extracted with MTBE(5×20 mL) and the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with dichloromethane/methanol(50:1 v/v) to give tert-butyl4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 2-29, 500 mg, 26%), LCMS: (ESI) m/z 444 [M+H]

Step 5.1-(4-Fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one trifluoroacetic acid salt

tert-Butyl4-((I-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate(Step 4, 500 mg, 1.13 mmol), dichloromethane (30 mL) and trifluoroaceticacid (3 mL) were added to a 50-mL round-bottom flask fitted with amagnetic stir bar and condenser. The resulting solution was stirred for2 h at 25° C. The resulting mixture was concentrated under vacuum togive1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-28) which was used withoutfurther purification. LCMS: (ESI) m/z 344 [M+H].

Table 12: The intermediates in Table 12 were synthesized according toprocedure described Example 21. All intermediates prepared according toIntermediate 2-28 were isolated as TFA salts, unless otherwisespecified. Some hydrazines were prepared according to general proceduredescribed below.

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar andthermometer was charged with corresponding aniline or amine (89.20mmol), hydrochloric acid (100 mL, 6N) followed by the addition of asolution of sodium nitrite (107.25 mmol) in water (20 mL) slowly addedwith stirring for 1 h at −20 to −10° C. To the reaction was slowly addeda solution of SnCl₂ (269.2 mmol) in hydrochloric acid (50 mL, 12N) andstirring continued for 1 h. The reaction was warmed to 23° C. and the pHwas adjusted to 8 with potassium hydroxide (6 N). The solids wereremoved by filtration. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the desired hydrazine.

TABLE 12 Procedure used in accordance with LCMS: (ESI) Intermediate No.:intermediate Precursor Used m/z [M + H] Intermediate 2-a.1-(4-bromophenyl)-5-((4- 2-28 (4- 404, 406hydroxypiperidin-4-yl)methyl)-1,5-dihydro- bromophenyl)hydrazine4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride salt Intermediate 29-xa.tert-butyl 4-((1-(4- 2-29 (4- 504, 506bromophenyl)-4-oxo-1,4-dihydro-5H- bromophenyl)hydrazinepyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4- hydrochloride salthydroxypiperidine-1-carboxylate Intermediate 2-16.5-((4-hydroxypiperidin- 2-28 3404-yl)methyl)-1-(p-tolyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-18. 5-((4-hydroxypiperidin- 2-28 3264-yl)methyl)-1-phenyl-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-19. 1-cyclopropyl-5-((4- 2-28 290hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-20. Methyl 3-(5-((4-2-28 384 hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1- yl)benzoate Intermediate 2-30.1-(3-bromophenyl)-5- 2-28 (3- 404, 406((4-hydroxypiperidin-4-yl)methyl)-1,5- bromophenyl)hydrazinedihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride saltIntermediate 30a tert-butyl 4-[[1-(3-   2.29 (3- 504, 506bromophenyl)-4-oxo-1H,4H,5H- bromophenyl)hydrazinepyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4- hydrochloride salthydroxypiperidine-1-carboxylate Intermediate 2-36.5-((4-hydroxypiperidin- 2-28 418 4-yl)methyl)-1-(4-phenoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-28a.1-(4-(tert- 2-28 382 butyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one Intermediate2-28b. 5-((4- 2-28 368 hydroxypiperidin-4-yl)methyl)-1-mesityl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4- one Intermediate 2-28c.5-((4-hydroxypiperidin- 2-28 368 4-yl)methyl)-1-(4-isopropylphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-28d. 5-((4-2-28 394 hydroxypiperidin-4-yl)methyl)-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-28f. 1-cyclohexyl-5-((4- 2-28 332hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-28g. 5-((4- 2-28 327hydroxypiperidin-4-yl)methyl)-1-(pyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one Intermediate 2-28h.5-((4- 2-28 404 hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfonyl)phenyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-28i. 5-((4-hydroxypiperidin- 2-28 3274-yl)methyl)-1-(pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-28j.1-(3,4-dichlorophenyl)- 2-28 394, 3965-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-28k. 5-((4-2-28 394 hydroxypiperidin-4-yl)methyl)-1-(3-(trifluoromethyl)phenyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-119a. 1-(4-chlorophenyl)-5- 2-28 360((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-94.5-[(4-hydroxypiperidin- 2-28 356 4-yl)methyl]-1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 926aa. 5-((4- 2-28(3- 356 Hydroxypiperidin-4-yl)methyl)-1-(3- methoxyphenyl)hydrazinemethoxyphenyl)-1H-pyrazolo[3,4- hydrochloride d]pyrimidin-4(5H)-one, TFAsalt salt Intermediate 2-93. 1-(3-bromo-4- 2-28 Hydrazine was 422fluorophenyl)-5-((4-hydroxypiperidin-4- prepared according toyl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- the general procedured]pyrimidin-4-one above Intermediate 2-150. tert-butyl 4-hydroxy-4- 2-29(4- 494 ([4-oxo-1-[4-(trifluoromethyl) phenyl]-(trifluoromethyl)phenyl)hydrazine 1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate Intermediate 2-2c. tert-butyl4-((1-(4- 2-29 4-chlorophenyl 460 chlorophenyl)-4-oxo-1,4-dihydro-5H-hydrazine pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate Intermediate 2-181aa. 5-((4- 2-28 (2-356 Hydroxypiperidin-4-yl)methyl)-1-(2- Methoxyphenyl)hydrazinemethoxyphenyl)-1,5-dihydro-4H- hydrochloridepyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-925aa. 1-(4-(4-chloro-1H-2-28 4-chloro-1-(4- 426, 428 pyrazol-1-yl)phenyl)-5-((4-hydrazinylphenyl)- hydroxypiperidin-4-yl)methyl)-1H- 1H-pyrazolepyrazolo[3,4-d]pyrimidin-4(5H)-one Intermediate 2-859aa. 5-((4- 2-28 (4-371 hydroxypiperidin-4-yl)methyl)-1-(4- (methylthio)phenyl)(methylthio)phenyl)-1,5-dihydro-4H- hydrazinepyrazolo[3,4-d]pyrimidin-4-one hydrochloride, prepared according toprocedure used for intermediate 2-28 utilizing (4-(methylthio)phenyl)aniline as starting material Intermediate 2-815a.5-((4- 2-28 3-nitrophenyl 370 hydroxypiperidin-4-yl)methyl)-1-(3-hydrazine nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin- hydrochloride4(5H)-one Intermediate 2-817a. 5-((4- 2-28 4-nitrophenyl 370hydroxypiperidin-4-yl)methyl)-1-(4- hydrazinenitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin- hydrochloride 4(5H)-oneIntermediate 2-678a. 1-(4-Bromo-3- 2-28 (4-bromo-3- 434, 436methoxyphenyl)-5-[(4-hydroxypiperidin-4- methoxyphenyl)hydrazine yl)methyl]-1H,4H,5H-pyrazolo[3,4- prepared from 4- d]pyrimidin-4-onebromo-3- methoxyaniline Intermediate 2-533a. 1-(4-ethylphenyl)-5- 2-28(4- 353 ((4-hydroxypiperidin-4-yl)methyl)-1H- ethylphenyl)hydrazinepyrazolo [3,4-d]pyrimidin-4(5H)-one hydrochloride prepared from 4-ethylaniline Intermediate 2-535a. 1-(4- 2-28 (4- 365cyclopropylphenyl)-5-[(4-hydroxypiperidin- cyclopropylphenyl)hydrazine4-yl)methyl]-1H,4H,5H-pyrazolo[3,4- hydrochloride d]pyrimidin-4-oneprepared from 4- cyclopropylaniline Intermediate 2-329a. 5-[(4- 2284-hydrazinyl-1- 329 hydroxypiperidin-4-yl)methyl]-1-(1-methyl-methyl-1H-pyrazole 1H-pyrazol-4-yl)-1H,5H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 2-331a. 1-(1-cyclopropyl-1H- 2-281-cyclopropyl-4- 355 pyrazol-4-yl)-5-((4-hydroxypiperidin-4-hydrazinyl-1H- yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- pyrazoled]pyrimidin-4-one Intermediate 2-330a. 5-((4- 2-28 4-hydrazinyl-1- 391hydroxypiperidin-4-yl)methyl)-1-(1-phenyl- phenyl-1H-pyrazole1H-pyrazol-4-yl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-oneIntermediate 2-320aa. 1-(3-bromo-4- 2-28 (3-bromo-4- 437, 439chlorophenyl)-5-((4-hydroxypiperidin-4- chlorophenyl)hydrazineyl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- HCl d]pyrimidin-4-oneIntermediate 2-258ba. 1-(3-bromo-4- 2-28 3-bromo-4- 422, 424fluorophenyl)-5-((4-hydroxypiperidin-4- fluorophenylhydrazineyl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- HCl d]pyrimidin-4-oneIntermediate 2-256. 1-(4-fluoro-3- 2-28 3-methoxy-4- 373methoxyphenyl)-5-((4-hydroxypiperidin-4- fluorophenylhydrazineyl)methyl)-1,5-dihydro-4H-pyrazolo[3,4- HCl d]pyrimidin-4-oneIntermediate 2-252A. 1-(6-fluoropyridin-3- 2-28 2-fluoro-5- 344yl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5- hydrazinylpyridinedihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one HCl

Example 22: Intermediate 2-922a.1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

Step 1. Tert-butyl4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate

) A 50-mL 3-necked round-bottom fitted with a nitrogen balloon, magneticstir bar condenser and thermometer was charged with tert-butyl4-[[1-(3-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate(Intermediate 30a, 294 mg, 0.58 mmol), 1,4-dioxane (10 mL),3-fluoro-1H-pyrazole (100 mg, 1.16 mmol), CuI (5.7 mg, 0.03 mmol),potassium carbonate (248 mg, 1.79 mmol) and(1R,2R)-cyclohexane-1,2-diamine (17 mg, 0.15 mmol) The resulting mixturewas stirred for 16 h at 100° C. under nitrogen. After cooling to 25° C.,the reaction was quenched with water (10 mL). The product was extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography eluting withdichloromethane/ethyl acetate (5:1-2:1, v/v) to give tert-butyl4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate(100 mg, 34%). LCMS: (ES) m/z 510 [M+H]

Step 2.1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

The title compound was prepared according to procedure outlined inExample 2, utilizingtert-butyl-4-([1-[3-(3-fluoro-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)-4-hydroxypiperidine-1-carboxylate(Step 1, 100 mg, 0.20 mmol), as starting material (110 mg, >95%). LCMS:(ES) m/z 410 [M+H].

The Intermediate below was synthesized according to the generalprocedure outlined above in Example 22.

TABLE 13 LCMS: (ESI, Intermediate No.: Precursor Used m/z) [M + H]⁺Intermediate 923a. 5-((4- Intermediate 29-xa tert-butyl 4-((1-(4- 557hydroxypiperidin-4-yl)methyl)-1-(4- bromophenyl)-4-oxo-1,4-dihydro-5H-(4-(trifluoromethyl)-1H-pyrazol-1-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4- yl)phenyl)-1,5-dihydro-4H-hydroxypiperidine-1-carboxylate and 4- pyrazolo[3,4-d]pyrimidin-4-one(trifluoromethyl)-1H-pyrazole

Example 23: Intermediate 926a.5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 50-mL 3-necked round-bottom fitted with a nitrogen balloon, magneticstir bar and thermometer was charged with5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(3-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(prepared according to procedure outlined in Example 6, utilizing5-[(4-hydroxypiperidin-4-yl)methyl]-1-(3-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one Intermediate 926aa, and1-methylcyclopropane-1-carboxylic acid)(800 mg, 1.74 mmol) anddichloromethane (5 mL). To the reaction was added boron tribromide indichloromethane (8.69 mL, 8.69 mmol, 1 M) dropwise with stirring at −50°C. After addition, the resulting solution was stirred for 16 h at 25° C.The reaction was quenched with water (20 mL). The product was extractedwith dichloromethane (3×30 mL) and the organic layers were combined,dried over anhydrous sodium sulfate and concentrated under vacuum toafford5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneas a light yellow solid (620 mg, 84%). LCMS: (ESI) m/z 424[M+H].

Example 24: Intermediate 2-33.1-(3-(Hydroxymethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt

1-(n-Tolyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

The title compound was prepared according to the procedure outlined inExample 21, Step 1 to Step 3, utilizing (3-methylphenyl)hydrazinehydrogen chloride as starting material (7.27 g, 64%). LCMS: (ESI) m/z227 [M+H].

Step 1.1-(3-(Dibromomethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

1-(m-Tolyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (500 mg, 2.21mmol), benzoyl peroxide (268 mg, 1.05 mmol), N-bromosuccinimide (473 mg,2.66 mmol) and carbon tetrachloride (50 mL) were added to a 100-mLround-bottom flask fitted with a nitrogen inlet, magnetic stir bar andcondenser. The resulting solution was stirred for 16 h at 100° C. Theresulting mixture was concentrated under vacuum to give1-(3-(dibromomethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onewhich was used in next step without further purification. LCMS: (ESI)nm/383, 385, 387 [M+H].

Step 2.3-(4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde

1-(3-(Dibromomethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Step 1, 800 mg, 2.08 mmol), calcium carbonate (10.0 g), 1,4-dioxane (50mL) and water (50 mL) were added to a 250-mL round-bottom flask fittedwith a nitrogen inlet, magnetic stir bar and condenser. The resultingsolution was heated to reflux for 2 h. The solids were filtered and thefiltrate was concentrated under vacuum to give3-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde whichwas used in next step without further purification. LCMS: (ESI) m/z 241[M+H].

Step 3.1-(3-(Hydroxymethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

3-(4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde (Step2, 500 mg, 2.08 mmol), methanol (30 mL) and sodium borohydride (70 mg,1.85 mmol, 0.89 equiv) were added to a 100-mL round-bottom flask fittedwith a nitrogen inlet, magnetic stir bar and condenser. The resultingsolution was stirred for 2 h at room temperature and then concentratedunder vacuum. The residue was purified by preparative TLC withdichloromethane/methanol (5:1 v/v) to provide1-(3-(hydroxymethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(120 mg, 24%), LCMS: (ESI) m/z 243 [M+H]

Step 4. tert-Butyl4-hydroxy-4-((1-(3-(hydroxymethyl)phenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate

The title compound was prepared according to the procedure described inExample 21, Step 4, utilizing1-(3-(hydroxymethyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Step 3, 300 mg, 1.24 mmol) as starting material followed bypurification by preparative TLC with dichloromethane/methanol (20:1 v/v)(80 mg, 14%). LCMS: (ESI) m/z 456 [M+H].

Step 5.1-(3-(Hydroxymethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt

The title compound was prepared according to the procedure described inExample 21, Step 4, utilizing tert-Butyl4-hydroxy-4-((1-(3-(hydroxymethyl)phenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylateas starting material (Step 4, 80 mg, 0.18 mmol and was used withoutfurther purification. LCMS: (ESI) m/z 356 [M+H]

Example 25: Intermediate 925a.4-chloro-1-(4-hydrazinylphenyl)-1H-pyrazole, HCl salt

Step 1. 4-Chloro-1-(4-nitrophenyl)-1H-pyrazole

A 250-mL 3-necked round-bottom fitted with a magnetic stir bar condenserand thermometer was charged with 4-chloro-1H-pyrazole (3 g, 29 mmol),N,N-dimethylformamide (80 mL), 1-fluoro-4-nitrobenzene (4 g, 28.4 mmol)and cesium carbonate (27.8 g, 85.3 mmol). The resulting mixture wasstirred for 1 h at 110° C. After cooling to 23° C., the reaction wasquenched with water (150 mL). The solids were collected by filtration,washed with water (50 mL) and dried in an oven to afford4-chloro-1-(4-nitrophenyl)-1H-pyrazole as a light yellow solid (6.2 g,96%). LCMS: (ESI) m/z 224, 226 [M+H].

Step 2. 4-(4-chloro-1H-pyrazol-1-yl)benzenamine

A 100-mL 3-necked round-bottom fitted with a magnetic stir bar condenserand thermometer was charged with 4-chloro-1-(4-nitrophenyl)-1H-pyrazole(Step 1, 3 g, 13.4 mmol), ethanol (10 mL), water (10 mL), iron (2.5 g,44.8 mmol), ammonium chloride (2.1 g, 39.3 mmol) and tetrahydrofuran (10mL). The resulting mixture was stirred for 1 h at 80° C. After coolingto 23° C., the solids were removed by filtration and the filtrate wasconcentrated under vacuum. The residue was diluted with water (100 mL)and the resulting mixture was extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford 4-chloro-1-(4-nitrophenyl)-1H-pyrazole as a light yellow solid(2.0 g, 77%). LCMS: (ESI) m/z 194, 196 [M+H].

Step 3. 4-chloro-1-(4-hydrazinylphenyl)-1H-pyrazole, hydrochloride salt

A 100-mL 3-necked round-bottom fitted with a magnetic stir bar andthermometer was charged with 4-(4-chloro-1H-pyrazol-1-yl)aniline (Step2, 2.0 g, 10.33 mmol), hydrochloric acid (12 N, 20 mL) and ethanol (10mL). The resulting solution was cooled to −20° C. followed by sodiumnitrite (1.06 g, 15.4 mmol) in water (5 mL) added dropwise with stirringat −20° C. After the mixture was stirred for 0.5 h at −10° C., tin(II)chloride (4.6 g, 20.4 mmol) was added in portions at −10° C. Theresulting solution was then stirred for additional 0.5 h at −10° C. Thesolids were collected by filtration and dried in an oven to afford theHCl salt of 4-chloro-1-(4-hydrazinylphenyl)-1H-pyrazole (800 mg crude,32%). LCMS: (ESI) m/z 209, 211 [M+H].

The Intermediates in Table 14 were prepared according to the proceduresoutlined in Example 25.

TABLE 14 Precursor Used (Step 2 and Step 3 LCMS: (ESI, Intermediate No.:for the synthesis) m/z) [M + H]⁺ Intermediate 2-1329. 4-1-methyl-4-nitro-1H- 113 hydrazinyl-1-methyl-1H- pyrazole pyrazole, HClsalt Intermediate 2-330a 4- 1-phenyl-4-nitro-1H- 175hydrazinyl-1-phenyl-1H- pyrazole pyrazole, HCl salt Intermediate 2-331a.1- 1-cyclopropyl-4-nitro- 139 cyclopropyl-4-hydrazinyl-1H- 1H-pyrazolepyrazole, HCl salt

Example 26. Intermediate 2-35.4-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzoic acid

Step 1. Methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate

Methyl 4-acetylbenzoate (1.00 g, 5.61 mmol), tetrahydrofuran (50 mL),tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 33 mL), andtrimethyl(trifluoromethyl)silane (2.40 g, 16.9 mmol) were added to a250-mL round-bottom flask at 0° C. The resulting solution was stirredfor 16 h at room temperature. Brine (10 mL) was added and the mixturewas extracted with ethyl acetate (3×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography elutingwith ethyl acetate/petroleum ether (15:85 v/v) to give methyl4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (850 mg, 53%). LCMS:(ESI) m/z 249 [M+H].

Step 2. 4-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzoic acid

Methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (Step 1, 450 mg,1.81 mmol), methanol (30 mL), lithium hydroxide (228 mg, 5.43 mmol) andwater (10 mL) were added to a 100-mL round-bottom flask. The resultingsolution was stirred for 2 h at 60° C. and then concentrated undervacuum. The pH value of the solution was adjusted to 4 with hydrogenchloride (1.0 M aqueous). The solution was then extracted withdichloromethane (3×10 mL) and the organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum togive 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (Intermediate2-35) which was used without further purification. LCMS: (ESI) m/z 233[M−H].

Example 27: Intermediate 2-36.Phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone

Trimethylsulfoxonium iodide (11.2 g, 51.0 mmol), dimethyl sulfoxide (15mL) and sodium hydride (60% in mineral oil, 157 mg, 6.54 mmol) wereadded to a 50-mL round-bottom flask fitted with a magnetic stir. Theresulting mixture was stirred for 30 min at room temperature.1-benzoylpiperidin-4-one (500 mg, 2.18 mmol) was added and the resultingsolution was stirred at room temperature for 4 h The reaction wasquenched by the addition of water (30 mL) and extracted withdichloromethane (3×30 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography using ethyl acetate toafford phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate2-36, 2.00 g, 54%). LCMS: (ESI) m/z 218 [M+H].

The Intermediates in Table 15 were prepared according to a proceduresimilar to that outlined in Example 27.

TABLE 15 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-46. (4- 1-(4- 236 Fluorophenyl)(1-oxa-6-Fluorobenzoyl)piperidin-4- azaspiro[2.5]octan-6- one yl)methanoneIntermediate 2-619a. 6- 1- 181 cyclopropanecarbonyl-1- (cyclopro- oxa-6-panecarbonyl)piperidin- azaspiro[2.5]octane 4-one

Example 28: Intermediate 2-40.3-(3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile

3-(4-Oxo-3,4-dihydro-7-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile(prepared from pyrrolo[2,3-d]pyrimidine and 3-cyanophenylboronic acid)(180 mg, 0.76 mmol),(4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate2-46, 180 mg, 0.77 mmol), cesium carbonate (745 mg, 2.29 mmol) and DMF(10 mL) were added to a 100-mL round-bottom flask fitted with a magneticstir bar and condenser. The resulting solution was stirred for 90 min at80° C. and then quenched by the addition of water (30 mL). The resultingsolution was extracted with ethyl acetate (4×40 mL) and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound whichwas used without further purification. LCMS: (ESI) m/z 472 [M+H].

Example 29: Intermediate 2-112.1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneTrifluoroacetic acid salt

Step 1. 4-Chloro-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar, condenser and thermometer was charged with4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.0 mmol),1-fluoro-4-iodobenzene (3.3 g, 14.9 mmol), potassium carbonate (3.58 g,25.9 mmol), 1,4-dioxane (40 mL), (1R,2R)-cyclohexane-1,2-diamine (300mg, 2.63 mmol) and cuprous iodide (493 mg, 2.59 mmol). The resultingsolution was stirred 16 h at 110° C. in an oil bath under nitrogen.After cooling to 25° C., the solids were removed by filtration and thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:2,v/v) to afford 4-chloro-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidineas a light yellow solid (1.0 g, 31%). LCMS: (ESI) m/z 248, 250 [M+H].

Step 2. 7-(4-Fluorophenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with4-chloro-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (Step 1, 800 mg,3.23 mmol), 1,4-dioxane (10 mL, 118.0 mmol), water (50 mL), potassiumcarbonate (4.2 g, 30.4 mmol) and 1,4-diazabicyclo[2.2.2]octane (727 mg,6.48 mmol). The resulting solution was stirred for 3 h at 80° C. in anoil bath. After cooling to 25° C., the reaction was quenched with water(70 mL). The product was extracted with ethyl acetate (3×50 mL) Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one as a whitesolid (700 mg, 94%). LCMS: (ESI) m/z 230 [M+H].

Step 3. tert-butyl4-((7-(4-fluorophenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

Title compound (500 mg, 43%). was prepared according to the procedureoutline in Example 21, Step 4, utilizing7-(4-fluorophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (Step 2, 600mg, 2.62 mmol) as starting material followed by column chromatographypurification eluting with methanol/dichloromethane (1:20, v/v) LCMS:(ESI) m/z 443 [M+H].

Step 4.7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneTrifluoroacetic acid salt

Title compound (470 mg, 95%) was prepared according to the procedureoutline in Example 21, Step 5, utilizing tert-butyl4-[[7-(4-fluorophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-1-carboxylate (Step 3, 500 mg, 1.13 mmol) asstarting material LCMS: (ESI) m/z 343 [M+H].

The Intermediate in Table 16 was prepared using a procedure similar tothat outlined for Example 30.

TABLE 16 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-2100. 7-(5- 4-chloro-7H-pyrrolo[2,3- 344fluoropyridin-2-yl)-3-((4- d]pyrimidine and hydroxypiperidin-4-2-bromo-5-fluoropyridine yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

Example 31: Intermediate 2-2101.3-((4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one,Trifluoroacetic acid salt

Step 1. 7-(3-Bromophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

A 250-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 13.0 mmol),(3-bromophenyl)boronic acid (3.12 g, 15.5 mmol), cupric acetate (708 mg,3.90 mmol), dichloromethane (60 mL) and pyridine (3.08 g, 38.94 mmol).The resulting solution was stirred for 5 h at 25° C. The solids wereremoved by filtration and the filtrate was concentrated under vacuum.The residue was diluted with water (50 mL) and the product was extractedwith dichloromethane (5×40 mL). The combined organic layers were washedwith hydrochloric acid (40 mL, 6N), dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:2,v/v) to give 7-(3-bromophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.0g, 50%). LCMS: (ESI) m/z 308, 310, 312[M+H].

Step 2. 7-(3-Bromophenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with7-(3-bromophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Step 1, 800 mg,2.59 mmol), 1,4-diazabicyclo[2.2.2]octane (581 mg, 5.18 mmol), potassiumcarbonate (3.37 g, 24.4 mmol), 1,4-dioxane (20 mL) and water (40 mL).The resulting solution was stirred 16 h at 100° C. in an oil bath. Aftercooling to 25° C., the reaction was diluted with water (50 mL). Theproduct was extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (9:1, v/v) to give7-(3-bromophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (600 mg, 80%).LCMS: (ESI) m/z 290, 292[M+H].

Step 3. Tert-butyl4-((7-(3-bromophenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with7-(3-bromophenyl)-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (300 mg, 1.03mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (264 mg,1.24 mmol), cesium carbonate (Step 2, 1.01 g, 3.10 mmol) andN,N-dimethylformamide (20 mL). The solution was stirred for 2 h at 80°C. in an oil bath. After cooling to 25° C., the reaction was quenchedwith water (50 mL). The product was extracted with ethyl acetate (5×30mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford tert-butyl4-[[7-(3-bromophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-1-carboxylate(230 mg). LCMS: (ESI) m/z 503, 505[M+H].

Step 4. Tert-butyl4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)phenyl)-4-oxo-4H-pyrrolo[2,3-d]pyrimidin-3(7H)-yl)methyl)piperidine-1-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with tert-butyl4-[[7-(3-bromophenyl)-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxypiperidine-1-carboxylate(Step 3, 170 mg, 0.34 mmol), 1-methylpiperazine (44.3 mg, 0.44 mmol),cesium carbonate (332.5 mg, 1.02 mmol), 1,4-dioxane (20 mL),tris(dibenzylideneacetone)dipalladium-chloroform adduct (35.2 mg, 0.03mmol) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (21 mg, 0.03mmol). The resulting solution was stirred for 16 h at 110° C. in an oilbath under nitrogen. After cooling to 25° C., the solids were removed byfiltration and the filtrate was diluted with water (100 mL). The productwas extracted with ethyl acetate (3×30 mL). The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by column chromatography cluting withdichloromethane/methanol (10:1, v/v) to give tert-butyl4-hydroxy-4-([7-[3-(4-methylpiperazin-1-yl)phenyl]-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl)piperidine-1-carboxylate(100 mg, 57%). LCMS: (ESI) m/z 523[M+H].

Step 5.3-((4-hydroxypiperidin-4-yl)methyl)-7-(3-(4-methylpiperazin-1-yl)phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one,TFA salt

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith tert-butyl4-hydroxy-4-([7-[3-(4-methylpiperazin-1-yl)phenyl]-4-oxo-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl)piperidine-1-carboxylate(Step 4, 100 mg, 0.19 mmol), dichloromethane (10 mL) and trifluoroaceticacid (1 mL). The resulting solution was stirred for 3 h at 25° C. Theresulting mixture was concentrated under vacuum to give the TFA salt of3-[(4-hydroxypiperidin-4-yl)methyl]-7-[3-(4-methylpiperazin-1-yl)phenyl]-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one(130 mg, >95%). LCMS: (ESI) m/z 423[M+H].

The Intermediates in Table 17 were prepared using a procedure similar tothat outlined for Example 31 and isolated as TFA salts.

TABLE 17 LCMS: (ESI) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-2102: 7-(4-fluorophenyl)-3-4-chloro-6-methyl-7H-pyrrolo[2,3- 357((4-hydroxypiperidin-4-yl)methyl)-6-methyl- d]pyrimidine and (4-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one Fluorophenyl)boronic acid.Synthesis does not include step 4 Intermediate 2-2103:3-((4-hydroxypiperidin- 4-chloro-7H-pyrrolo[2,3- 4104-yl)methyl)-7-(3-morpholinophenyl)-3,7- d]pyrimidine, 3-bromoboronicdihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one acid and morpholineIntermediate 2-2105: 3-((4-hydroxypiperidin- 4-chloro-7H-pyrrolo[2,3-410 4-yl)methyl)-7-(4-morpholinophenyl)-3,7- d]pyrimidine,4-bromoboronic dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one acid andmorpholine Intermediate 872a. 3-((4-hydroxypiperidin-4-4-chloro-7H-pyrrolo[2,3- 422 yl)methyl)-7-(3-(piperidin-1-ylmethyl)d]pyrimidine and (3- phenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-formylphenyl)boronic acid.* one Intermediate 2-2105: 7-(4-fluoro-3-4-chloro-7H-pyrrolo[2,3- 440 (piperidin-1-ylmethyl)phenyl)-3-((4-d]pyrimidine and (3-formyl-4- hydroxypiperidin-4-yl)methyl)-3,7-dihydro-fluorophenyl)boronic acid.* 4H-pyrrolo[2,3-d]pyrimidin-4-one*Introduction of piperidine was achieved under reductive aminationconditions when a solution of3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzaldehyde Intermediate(600 mg, 2.33 mmol), piperidine (198 mg, 2.33 mmol), dichloromethane (50mL), and glacial acetic acid (0.2 mL) was treated with sodiumcyanoborohydride (294 mg, 4.68 mmol) at 0° C.

Example 32: Intermediate 2-47.3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-onetrifluoroacetic acid salt

Step 1. tert-Butyl4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 13.0 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (7.80 g, 38.8 mmol),triphenylphosphine (4.52 g, 17.2 mmol) and tetrahydrofuran (120 mL) wereadded to a 500-mL 3-necked round-bottom flask fitted with a nitrogeninlet and magnetic stir bar. A solution of diethyl azodicarboxylate(6.80 g, 39.1 mmol) in toluene (30 mL) was then added dropwise withstirring at room temperature. The resulting solution was stirred for 4 hat room temperature, quenched by the addition of water (100 mL) andextracted with dichloromethane (3×100 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography using ethyl acetate/petroleum ether (1:1 v/v) to affordtert-butyl4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(2.50 g, 57%). LCMS: (ESI) m/z 337 [M+H].

Step 2. tert-Butyl4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

tert-Butyl4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(Step 1, 2.50 g, 7.42 mmol), DABCO (1.70 g, 15.2 mmol), potassiumcarbonate (10.2 g, 73.8 mmol), 1,4-dioxane (80 mL) and water (40 mL)were added to a 250-mL round-bottom flask fitted with a magnetic stirbar and condenser. The resulting solution was stirred for 4 h at 60° C.,diluted with water (50 mL) and extracted with ethyl acetate (5×50 mL).The organic layers were combined, washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography usingdichloromethane/methanol (10/1 v/v) to afford tert-butyl4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(1.30 g, 55%). LCMS: (ESI) m/z 319 [M+H]

Step 3. tert-Butyl4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

tert-butyl4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(Step 2, 600 mg, 1.88 mmol),(4-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone (Intermediate2-46, 300 mg, 1.28 mmol), cesium carbonate (1.25 g, 3.83 mmol) and DMF(50 mL) were added to a 100-mL round-bottom flask fitted with a magneticstir bar and condenser. The resulting solution was stirred for 2 h at80° C. and then quenched by the addition of water (30 mL). The resultingsolution was extracted with ethyl acetate (4×50 mL) and the organiclayers were combined, washed with brine (100 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC with methanol/dichloromethane(1:20 v/v) to afford tert-butyl4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(600 mg, 58%). LCMS: (ESI) m/z 554 [M+H].

Step 4.3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-onetrifluoroacetic acid salt

tert-Butyl4-(3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate(Step 3, 600 mg, 1.08 mmol), dichloromethane (30 mL) and trifluoroaceticacid (6 mL) were added to a 100-mL round-bottom flask fitted with amagnetic stir bar. The resulting solution was stirred for 2 h at roomtemperature and then concentrated under reduced pressure to give3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-47) which was used in nextstep without further purification. LCMS: (ESI) m/z 454 [M+H].

Example 33: Intermediate 2-57. 4-(pyrrolidin-1-ylmethyl)benzoic acid

Step 1. Methyl 4-(pyrrolidin-1-ylmethyl)benzoate

A 250-mL round-bottom flask was charged with methyl 3-formylbenzoate (1g, 6.09 mmol) pyrrolidine (433 mg, 6.09 mmol) and chloroform (100 mL).The resulting solution was stirred at 0° C. for 1 h. Sodium borohydride(70 mg, 1.85 mmol) and acetic acid (5 mL) were added to the mixture at0° C. The resulting solution was stirred 16 h at 23° C. The pH of thesolution was adjusted to 8 with saturated sodium bicarbonate solution(30 mL) and extracted with dichloromethane (3×100 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:4 v/v) toafford methyl 4-(pyrrolidin-1-ylmethyl)benzoate (500 mg, 37%) as acolorless oil. LCMS: (ESI) m/z 220 [M+H].

Step 2. 3-(Pyrrolidin-1-ylmethyl)benzoic acid

A 100-mL round-bottom flask was charged with methyl3-(pyrrolidin-1-ylmethyl) benzoate (500 mg, 2.28 mmol), methanol (20mL), lithium hydroxide (274 mg, 11.44 mmol) and water (5 mL). Theresulting solution was stirred for 1 h at 40° C. The pH of the solutionwas adjusted to 6 with hydrochloric acid (6.0 M). The solids werecollected by filtration, washed with ethyl acetate (3×20 mL) and driedin an oven to afford 4-(pyrrolidin-1-ylmethyl)benzoic acid as a whitesolid which was used without further purification (Intermediate 2-57,650 mg, >95%). LCMS (ESI) m/z 206 [M+H].

The Intermediates in Table 18 were synthesized according to theprocedures above.

TABLE 18 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-58. 4- methyl 3-formylbenzoate 222(morpholinomethyl)benzoic and morpholine acid Intermediate 2-176. 4-[(6-ethyl 4-oxocyclohexane-1- 239 fluoropyridin-2-yl)amino] carboxylate and6- cyclohexane-1- fluoropyridin-2-amine carboxylic acid

Example 34: Intermediate 2-59.5-(Piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylic acid

Step 1. Ethyl 2-oxo-2-(2-(piperidine-1-carbonyl)hydrazinyl)acetate

A 25-mL round-bottom flask was charged with piperidine-1-carbonylchloride (178 mg, 1.21 mmol), ethyl (hydrazinecarbonyl)formate (132 mg,1.00 mmol), triethylamine (152 mg, 1.50 mmol) and tetrahydrofuran (10mL). The resulting solution was stirred 16 h at 60° C. The reaction wasthen quenched by the addition of 20 mL of water and extracted withdichloromethane (2×10 mL). The organic layers were combined and washedwith water (10 mL) and brine (10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (5:1 to 20:1 v/v) to afford ethyl2-oxo-2-(2-(piperidine-1-carbonyl hydrazinyl)acetate (200 mg, 82%) as awhite solid. LCMS (ESI) m/z 244 [M+H].

Step 2. Ethyl 5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate

A 25-mL round-bottom flask was charged with2-oxo-2-(2-(piperidine-1-carbonyl hydrazinyl)acetate (Step 1, 100 mg,0.41 mmol), 4-methylbenzene-1-sulfonyl chloride (78 mg, 0.41 mmol),triethylamine (50 mg, 0.49 mmol) and dichloromethane (15 mL). Theresulting solution was stirred 16 h at 23° C. The reaction was thenquenched by the addition of water (10 mL) and the resulting mixture wasextracted with dichloromethane (3×10 mL). The organic layers werecombined and washed with water (10 mL) and brine (10 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography eluting with ethylacetate/petroleum ether (2:1 to 10:1 v/v) to afford ethyl5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate as an off-white solid(80 mg, 87%). LCMS: (ESI) r/z 226 [M+H].

Step 3. 5-(Piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylic acid

A 25-mL round-bottom flask was charged with ethyl5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate (Step 2, 80 mg, 0.35mmol), lithium hydroxide (17 mg, 0.70 mmol), water (5 mL) andtetrahydrofuran (5 mL). The resulting solution was stirred for 3 h at23° C. The pH of the solution was adjusted to 5-6 with hydrochloric acid(6.0 M). The resulting solution was extracted with dichloromethane (2×30mL) and the organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford5-(piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylic acid (Intermediate2-59, 60 mg, 87%) as an off-white solid which was used directly in thenext step without further purification. LCMS (ESI) m/z 198 [M+H].

The Intermediate in Table 19 below was synthesized according to theprocedures above, starting with the chloride described in Table 19.

TABLE 19 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-76. 5- cyclopropanecarbonyl 155 cyclopropyl-1,3,4-chloride oxadiazole-2- carboxylic acid

Example 35: Intermediate 2-60. 4-(1H-pyrazol-1-yl)benzoic acid

Step 1. 4-(1H-pyrazol-1-yl)benzonitrile

A 100-mL round-bottom flask was charged with 4-fluorobenzonitrile (2 g,16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide(20 mL) and 1H-pyrazole (2.24 g, 32.90 mmol). The resulting solution wasrefluxed for 2 h. The solids were removed by filtration and the filtratewas concentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4v/v) to afford 4-(1H-pyrazol-1-yl)benzonitrile as a yellow oil (1.3 g,47%). LCMS: (ESI) nm/z 170 [M+H].

Step 2. 4-(1H-pyrazol-1-yl)benzoic acid

A 250-mL round-bottom flask was charged with4-(1H-pyrazol-1-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40mL), water (40 mL) and sodium hydroxide (705 mg, 17.63 mmol). Theresulting solution was stirred at 105° C. 16 h and then concentratedunder vacuum. The residue was diluted with water (30 mL) and extractedwith ethyl acetate (50 mL). The pH of the aqueous phase was adjusted to5 with hydrochloric acid (6.0 M). The solids were collected byfiltration, washed with water (10 mL) and dried in an oven to afford4-(1H-pyrazol-1-yl)benzoic acid as a light yellow solid (Intermediate2-60, 1 g, 45%). LCMS: (ESI) m/z 189 [M+H].

The Intermediates in Table 20 were prepared according to the procedureoutlined in Example 35.

TABLE 20 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediates 862a and 862b. Tert-butyl2- Methyl 4-fluorobenzoate andtert- 344 (4-(methoxycarbonyl)phenyl)pyrrolo[3,4-butyl-1H,4H,5H,6H-pyrrolo[3,4- c]pyrazole-5(2H,4H,6H)-carboxylate andc]pyrazole-5-carboxylate tert-butyl 1-(4-(methoxycarbonyl)phenyl)pyrrolo[3,4-c] pyrazole-5(1H,4H,6H)-carboxylateIntermediates 2-238a. 4-(4-cyano-1H- ethyl 4-bromobenzoate and 1H- 214pyrazol-1-yl)benzoic acid pyrazole-4-carbonitrile Intermediates 2-880.(S)-4-(3- Ethyl 4-fluorobenzoate and (S)- 208Hydroxypyrrolidin-1-yl)benzoic acid pyrrolidin-3-ol Intermediates 2-60aand 2-60b. 4-(2H- 4-fluorobenzonitrile and 1,2,3- 188 [M − H]1,2,3-triazol-2-yl)benzoic acid and 4-(1H- triazole1,2,3-triazol-1-yl)benzoic acid

Example 36: Intermediate 2-336aa. 4-(1H-1,2,3-triazol-1-yl)benzenamineand 4-(1H-1,2,3-triazol-2-yl)benzenamine

Step 1. 1-(4-nitrophenyl)-1H-1,2,3-triazole and2-(4-nitrophenyl)-2H-1,2,3-triazole

A 250-mL 3-necked round-bottom flask was charged with 2H-1,2,3-triazole(1.061 g, 15.4 mmol), N,N-dimethylformamide (60 mL),1-fluoro-4-nitrobenzene (2 g, 14.2 mmol) and K₂CO₃ (5.87 g, 42.2 mmol).The resulting solution was stirred for 16 h at 110° C. in an oil bathand cooled to 25° C. The reaction was diluted with water (50 mL). Theproduct was extracted with ethyl acetate (5×30 mL) The combined organiclayers were concentrated under vacuum. The residue was purified bypreparative HPLC* to afford the mixture of1-(4-nitrophenyl)-1H-1,2,3-triazole and2-(4-nitrophenyl)-2H-1,2,3-triazole (1:3) (1.6 g, 59%) as a yellowsolid. LCMS: (ESI) m/z 191 [M+H]. *Column: silica gel. Mobile phase A:ethyl acetate/Mobile phase B: petroleum ether. Gradient: 10% B to 50% Bover 35 min. Detector: 254 nm.

Step 2. 4-(1H-1,2,3-triazol-1-yl)benzenamine and4-(1H-1,2,3-triazol-2-yl)benzenamine

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with the mixture of1-(4-nitrophenyl)-1H-1,2,3-triazole and2-(4-nitrophenyl)-2H-1,2,3-triazole (Step 1, 1 g, 5.26 mmol), ethanol(30 mL), water (30 mL), Fe (1.5 g, 26.8 mmol), ammonium chloride (832mg, 15.6 mmol). The resulting solution was stirred for 3 h at 80° C. inan oil bath. The reaction was cooled to 23° C. and the solids wereremoved by filtration. The filtrate was concentrated under vacuum andthe residue was diluted with water (30 mL). The product was extractedwith ethyl acetate (5×30 mL). The combined organic layers wereconcentrated under vacuum to afford a mixture of4-(1H-1,2,3-triazol-1-yl)benzenamine and4-(1H-1,2,3-triazol-2-yl)benzenamine (800 mg, 94%) as a yellow solid.LCMS: (ESI) m/z 161 [M+H].

Example 37: Intermediate 2-61.2-(piperidin-1-yl)-1,3-oxazole-5-carboxylic acid

Step 1. Ethyl 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylate

A 5-ml, microwave tube was charged with ethyl2-bromo-1,3-oxazole-5-carboxylate (500 mg, 2.27 mmol), piperidine (219mg, 2.57 mmol) and (trifluoromethyl)benzene (2 mL). The final reactionmixture was irradiated with microwave radiation for 30 min at 150° C.The resulting solution was cooled to 23° C. and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:1 v/v) to afford ethyl2-(piperidin-1-yl)-1,3-oxazole-5-carboxylate as a white solid (400 mg,78%). LCMS: (ESI) m/z 225 [M+H].

Step 2. 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylic acid

A 100-ml round-bottom flask was charged with ethyl2-(piperidin-1-yl)-1,3-oxazole-5-carboxylate (Step 1, 400 mg, 1.78mmol), lithium hydroxide (129 mg, 5.39 mmol), methanol (15 mL) and water(2 mL). The resulting solution was stirred for 3 h at 55° C. Theresulting solution was diluted with 30 mL of water and the pH wasadjusted to 5-6 with hydrochloric acid (6.0 M). The mixture wasextracted with ethyl acetate (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford 2-(piperidin-1-yl)-1,3-oxazole-5-carboxylic acid(Intermediate 2-61, 350 mg, 99%) as a light yellow oil which was useddirectly in the next step without further purification. LCMS: (ESI) m/z197 [M+H].

The Intermediates in Table 21 below were synthesized according to theprocedures outlined above.

TABLE 21 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-62. 4-(morpholinomethyl)benzoic methyl 2-bromo-1,3- 199acid oxazole-5-carboxylate and morpholine Intermediate 2-165.2-(4-Hydroxypiperidin-1- methyl 2-bromo-1,3- 213 yl)oxazole-5-carboxylicacid oxazole-5-carboxylate and 4-hydroxypiperidine Intermediate 2-117.2-(4-Methylpiperazin-1- methyl 2-bromo-1,3- 212 yl)oxazole-5-carboxylicacid oxazole-5-carboxylate and 1-methylpiperazine Intermediate 2-881.2-(Cyclopropylamino)-1,3- methyl 2-bromo-1,3- 167 oxazole-5-carboxylateand oxazole-5-carboxylic acid cyclopropylamine

Example 37a: Intermediate 2-64. 1-benzyl-1H-pyrazole-5-carboxylic acid

Step 1. 1-benzyl-1H-pyrazole

A 250-mL, round-bottom flask was charged with 1H-pyrazole (1 g, 14.69mmol), potassium hydroxide (1.2 g, 21.39 mmol), potassium carbonate (3g, 21.71 mmol), tetrabutylammonium bromide (7 g, 21.71 mmol), xylene (50mL) and (bromomethyl)benzene (2.5 g, 14.62 mmol). The resulting mixturewas stirred 16 h at 23° C. The reaction was then quenched by theaddition of 150 mL of water. The resulting mixture was extracted withethyl acetate (3×80 mL) and washed with 200 mL of water. The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:3 v/v) toafford 1-benzyl-1H-pyrazole as a light yellow solid (1.3 g, 56%). LCMS:(ESI) m/z 159 [M+H].

Step 2. 1-benzyl-1H-pyrazole-5-carboxylic acid

A 100-mL 3-necked round-bottom flask equipped with a nitrogen balloonand thermometer was charged with 1-benzyl-1H-pyrazole (Step 1, 400 mg,2.53 mmol) and tetrahydrofuran (25 mL). To the reaction was addedn-butyl lithium (2.5 mL, 1.0 mmol) at −78° C. The resulting mixture wasstirred for 1 hour at −78° C. in a dry ice bath before carbon dioxidewas bubbled into the mixture. The resulting solution was stirred foradditional 1 hour at −78° C. in a dry ice bath and then quenched by theaddition of 30 mL of water and extracted with ethyl acetate (3×40 mL).The organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford1-benzyl-1H-pyrazole-5-carboxylic acid (including by product:2-phenyl-2-(1H-pyrazol-1-yl)acetic acid) as a white oil which was useddirectly in the next step without further purification (Intermediate2-64, 150 mg, 29%). LCMS: (ESI) m/z 203 [M+H].

Example 38: Intermediate 2-71. 4-(1H-pyrazol-1-yl)cyclohexanecarboxylicacid yl)cyclohexanecarboxylic acid

Step 1. ethyl 4-(tosyloxy)cyclohexanecarboxylate

A 250-mL round-bottom flask was charged with ethyl4-hydroxycyclohexane-1-carboxylate (3 g, 17.42 mmol),4-methylbenzene-1-sulfonyl chloride (5 g, 26.23 mmol), dichloromethane(50 mL) and triethylamine (5.28 g, 52.18 mmol). The resulting solutionwas stirred for 4 h at 23° C. The reaction was then quenched with water(50 mL). The mixture was extracted with dichloromethane (2×50 mL) andthe organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:10v/v) to afford ethyl 4-(tosyloxy)cyclohexanecarboxylate as a yellowsolid (2.7 g, 47%). LCMS: (ESI) m/z 327 [M+H].

Step 2. ethyl 4-(1H-pyrazol-1-yl)cyclohexanecarboxylate

A 100-mL round-bottom flask was charged with ethyl 4-(tosyloxy)cyclohexanecarboxylate (Step 1, 2 g, 6.13 mmol), 1H-pyrazole (626 mg,9.20 mmol), N,N-dimethylformamide (60 mL) and cesium carbonate (6 g,18.42 mmol). The resulting solution was stirred 16 h at 80° C. Aftercooling to room temperature, the reaction was then quenched by theaddition of water (60 mL) and extracted with ethyl acetate (3×60 mL).The organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:1v/v) to afford ethyl 4-(1H-pyrazol-1-yl)cyclohexanecarboxylate as ayellow solid (400 mg, 29%). LCMS: (ESI) m/z 223 [M+H].

Step 3. 4-(1H-pyrazol-1-yl)cyclohexanecarboxylic acid

The title compound was prepared according to procedure outlined inExample 8, Step 2, utilizing ethyl 4-(1H-pyrazol-1-yl)cyclohexanecarboxylate (100 mg, 0.45 mmol) as starting material(Intermediate 2-71, 40 mg, 46%) which was used without furtherpurification. LCMS: (ESI) m/z 195 [M+H].

Example 39: Intermediate 2-72. 4-(3,4-Dihydro-2H-pyrrolo[2,1-b][1,3]oxazin-8-yl)benzoic acid

Step 1. Methyl4-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)benzoate

A 50-mL round-bottom flask was charged with methyl4-(2-methoxy-2-oxoethyl) benzoate (1 g, 4.80 mmol),(dimethoxymethyl)dimethylamine (571 mg, 4.79 mmol) andN,N-dimethylformamide (15 mL). The resulting solution was stirred for 4h at 60° C. After cooling to 23° C., the reaction was quenched withwater (30 mL) and the product was extracted with ethyl acetate (3×30mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:1 v/v) to afford methyl4-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)benzoate as a yellowsolid (800 mg, 63%). LCMS: (ESI) m/z 264 [M+H].

Step 2. Methyl 4-(5-oxo-2,5-dihydro-1H-pyrazol-4-yl)benzoate

A 50-mL round-bottom flask was charged with methyl4-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)benzoate (Step 1, 800mg, 3.04 mmol), hydrazine hydrochloride (310 mg, 4.56 mmol),triethylamine (921 mg, 9.10 mmol) and ethanol (20 mL). The resultingsolution was stirred for 2 h at 90° C. and cooled to 23° C. beforeconcentrating the solution under vacuum. The residue was purified bypreparative thin layer chromatography eluting withdichloromethane/methanol (10:1 v/v) to afford methyl4-(5-oxo-2,5-dihydro-1H-pyrazol-4-yl)benzoate as a yellow solid (520 mg,78%). LCMS: (ESI) m/z 219 [M+H].

Step 3. Methyl 4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)benzoate

A 50-mL round-bottom flask was charged with methyl4-(5-oxo-2,5-dihydro-1H-pyrazol-4-yl)benzoate (Step 2, 250 mg, 1.15mmol), 1,3-dibromopropane (232 mg, 1.15 mmol), cesium carbonate (1.12 g,3.44 mmol) and DMF (15 mL). The resulting solution was stirred 16 h at80° C. The mixture was allowed to cool to 23° C. and then quenched withwater (15 mL) and extracted with ethyl acetate (3×20 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparative thinlayer chromatography eluting with dichloromethane/methanol (20:1 v/v) toafford methyl 4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)benzoate as a yellow solid (100 mg, 34%). LCMS:(ESI) m/z 259 [M+H].

Step 4. 4-(3, 4-Dihydro-2H-pyrrolo[2,1-b][1,3]oxazin-8-yl)benzoic acid

The title compound was prepared according to procedure outlined inExample 8, Step 2, utilizing methyl 4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)benzoate (Step 3, 100 mg,0.39 mmol) as starting material (Intermediate 2-72, 80 mg, 85%). LCMS:(ESI) m/z 245 [M+H].

The Intermediate in Table 22 below was synthesized according to theprocedures outlined above.

TABLE 22 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-73. 4-(2,3- methyl 4-(2-methoxy-2- 231Dihydropyrazolo[5,1- oxoethyl) benzoate b]oxazol-7- yl)benzoic acid

Example 40: Intermediate 2-74.4-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid

Step 1. Methyl4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoate

A 100-mL round-bottom flask equipped with a nitrogen balloon was chargedwith [4-(methoxycarbonyl)phenyl] boronic acid (400 mg, 2.22 mmol),3-bromo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidine (300 mg, 1.48 mmol),potassium carbonate (946.7 mg, 4.46 mmol), toluene (20 mL),tris(dibenzylideneacetone)dipalladium-chloroform adduct (136 mg, 0.15mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl) phosphine (61 mg, 0.15mmol) and cesium fluoride (22.6 mg, 0.15 mmol) The resulting solutionwas stirred 16 h at 120° C. in an oil bath. The reaction mixture wasallowed to cool to 23° C. and the solids were filtered. The filtrate wasconcentrated under vacuum and the residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (3:2 v/v) toafford methyl4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoate as a yellowsolid (160 mg, 42%). LCMS: (ESI) m/z 258 [M+H].

Step 2. 4-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid

The title compound was prepared according to procedure outlined inExample 10, Step 2, utilizing methyl4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)benzoate (Step 1, 120mg, 0.47 mmol), as starting material purified by column chromatographyeluting with dichloromethane/methanol (20:1 v/v) (Intermediate 2-74.80mg, 71%). LCMS: (ESI) m/z 244 [M+H].

The Intermediate in Table 23 below was synthesized according to theprocedures outlined above. 3-bromo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrimidine(40 mg, 0.20 mmol) was alkylated prior to following the procedures abovewith iodomethane (28 mg, 0.20 mmol) in DMF (10 mL) in the presence ofNaH (9 mg, 0.23 mmol).

TABLE 23 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-75. 4-(4- 3-bromo-4H,5H,6H,7H- 231 Methyl-4,5,6,7-pyrazolo[1,5-a]pyrimidine and tetrahydropyrazolo[1,5-[4-(methoxycarbonyl)phenyl] a]pyrimidin-3- boronic acid yl)benzoic acid

Example 41: Intermediate 2-77. 5-benzyloxazole-4-carboxylic acid

Step 1. Ethyl 5-benzyloxazole-4-carboxylate

A 100-mL round-bottom flask was charged with 2-phenylacetyl chloride(0.500 g, 3.23 mmol), ethyl 2-(methylideneamino)acetate (0.366 g, 3.18mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.492 g, 3.23 mmol),tetrahydrofuran (30 mL). The resulting solution was stirred for 16 h at23° C. and then diluted with water (30 mL). The product was extractedwith of ethyl acetate (3×20 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtrated and concentrated under vacuumto afford ethyl 5-benzyloxazole-4-carboxylate (0.070 g, 9%) as a whitesolid which was directly used in the next step without purification.LCMS: (ESI) m/z 232 [M+H].

Step 2. 5-benzyloxazole-4-carboxylic acid

The title compound was prepared according to procedure outlined inExample 10, Step 2, utilizing 5-benzyloxazole-4-carboxylate (Step 1,0.070 g, 0.30 mmol) as starting material which was directly used in thenext step without purification (Intermediate 2-77, 0.060 g, 49%). LCMS:(ESI) m/z 204 [M+H].

Example 42: Intermediate 2-78.1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylic acid

Step 1. Ethyl 1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylate

A 100-mL round-bottom flask was charged withethyl-1H-pyrrole-2-carboxylate (617 mg, 4.43 mmol),1-(bromomethyl)-4-fluorobenzene (1.0 g, 5.29 mmol), cesium carbonate(4.3 g, 13.20 mmol) and N,N-dimethylformamide (20 mL). The resultingsolution was stirred for 16 h at 60° C. in an oil bath. After cooling to23° C., the reaction was quenched with water (30 mL). The resultingsolution was extracted with ethyl acetate (3×30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtrated andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) toafford ethyl 1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylate (1.04g, 95%). LCMS: (ESI) m/z 248 [M+H].

Step 2. 1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylic acid

The title compound was prepared according to procedure outlined inExample 8, Step 2, utilizing ethyl1-[(4-fluorophenyl)methyl]-1H-pyrrole-2-carboxylate (Step 1, 1.04 g,4.21 mmol) as starting material (Intermediate 2-78, 300 mg, 33%) whichwas used without further purification. LCMS (ESI) m/z 220 [M+H].

Table 23a: The Intermediates in Table 23a below were also synthesizedaccording to the procedures outlined above.

TABLE 23a MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-79. 1-(2,6-Difluorobenzyl)-ethyl-1H-pyrrole-2-carboxylate 238 1H-pyrrole-2-carboxylic acid and1-(bromomethyl)-2,6- difluorobenzene Intermediate 2-80. 1-[(3-ethyl-1H-pyrrole-2-carboxylate 220 fluorophenyl)methyl]-1H-pyrrole-2-and 1-(bromomethyl)-3- carboxylic acid fluorobenzene Intermediate 2-81.1-(2-fluorobenzyl)-1H- ethyl-1H-pyrrole-2-carboxylate 220pyrrole-2-carboxylic acid and 1-(bromomethyl)-2- fluorobenzeneIntermediate 2-143. 1-(2-fluorobenzyl)- ethyl 1H-pyrrole-2-carboxylate220 1H-pyrrole-2-carboxylic acid and 1-(bromomethyl)-2- fluorobenzene

Example 43: Intermediate 2-85. tert-butyl4-hydroxy-4-[(1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]piperidine-1-carboxylate

Step 1. Tert-butyl 4-ethylidenepiperidine-1-carboxylate

A 250-mL 3-necked round-bottom flask equipped with a balloon filled withnitrogen was charged with bromo(ethyl)triphenyl-5-phosphane (9.3 g,25.05 mmol), and tetrahydrofuran (100 mL). To the reaction was addedn-butyl lithium (2.5M in hexane, 11 mL, 27.5 mmol) dropwise withstirring at −78° C. for 1 h before adding tert-butyl4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) as a solution intetrahydrofuran (20 mL) at −20° C. Stirring was continued for 1 h at−20° C. before quenching with water (30 mL). The product was extractedwith ethyl acetate (5×50 mL). The combined organic layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:9 v/v) to afford tert-butyl4-ethylidenepiperidine-1-carboxylate (4.2 g, 79%) as a light yellowsolid. LCMS (ESI) m/z 212 [M+H].

Step 2. tert-butyl-2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

A 250-mL, round-bottom flask was charged with tert-butyl4-ethylidenepiperidine-1-carboxylate (Step 1, 4.2 g, 19.88 mmol),3-chloroperoxybenzoic acid (5.16 g, 29.9 mmol) and dichloromethane (100mL). The resulting solution was stirred for 3 h at room temperature andquenched with aqueous saturated sodium sulfite solution (10 mL). The pHwas adjusted to 7 with sodium bicarbonate (6 M) and the product wasextracted with dichloromethane (3×100 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography elutingwith ethyl acetate/petroleum ether (1:10 to 1:5 v/v) to affordtert-butyl 2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (3.8 g,84%) b as a colorless liquid. LCMS (ESI) m/z 228 [M+H].

Step 3. tert-butyl4-hydroxy-4-(1-(1-(4-methoxyphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)piperidine-1-carboxylate

The title compound was prepared according to the procedure outlines inExample 28 utilizing1-(4-methoxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (preparedaccording to the procedure outline in Example 21, Step 3, usingp-methoxy hydrazine hydrochloride as the starting material, 2.3 g, 9.49mmol) and tert-butyl 2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate(Step 2, 2.6 g, 11.44 mmol), followed by column chromatographypurification eluting with ethyl acetate/petroleum ether (1:1 v/v) (3.8g, 81%) LCMS (ESI) m/z 470 [M+H]. The racemic product (tert-butyl4-hydroxy-4-(1-(1-(4-methoxyphenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)piperidine-1-carboxylate) (2.25 g) was further purified byprep-SFC* to afford 1-tert-butyl4-hydroxy-4-[(1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]piperidine-1-carboxylate(Intermediate 2-85, 629.1 mg, retention time: 2.02 min, 14.3%,stereochemistry unconfirmed) as a white solid. 1H NMR (300 MHz, DMSO-d₆)δ 0.95-1.19 (m, 1H), 1.20-1.44 (m, 13H), 1.45-1.71 (m, 2H), 2.79-3.15(m, 2H), 3.50-3.81 (m, 2H), 3.83 (s, 3H), 4.85-5.10 (d, J=7.5 Hz, 1H),5.11 (s, 1H), 7.00-7.18 (m, 2H), 7.81-8.00 (m, 2H), 8.32 (s, 1H), 8.39(s, 1H). LCMS (ESI) m/z 470 [M+H].

1-tert-butyl-4-hydroxy-4-[(1S)-1-[1-(4-methoxyphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]ethyl]-1[3],3-oxazocan-2-one(Intermediate 2-85, 614 mg, 14%) as a white solid, Retention time: 1.46min, stereochemistry unconfirmed). ¹H NMR (300 MHz, DMSO-d₆) δ 0.92-1.11(m, 1H), 1.17-1.44 (m, 13H), 150-1.75 (m, 2H), 2.80-3.18 (m, 2H),3.45-3.80 (m, 2H), 3.82 (s, 3H), 4.85-5.02 (m, 1H), 5.11 (brs, 1H),6.92-7.22 (m, 2H), 7.75-8.05 (m, 2H), 8.32 (s, 1H), 8.39 (s, 1H). MS(ESI, m/z) 470 [M+H]+. *SFC column: CHIRALCEL OJ-3, 4.6×50 mm, 3 um.Mobile Phase A 0.1% aqueous DEA/Mobile phase B: methanol, Flow rate: 4ml/min. Detector: 220 and 254 nm.

The Intermediate in Table 24 below was synthesized according to theprocedures outlined in Example 43.

TABLE 24 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-87. 1-(4- 1-(4-fluorophenyl)- 358 fluorophenyl)-5-(1-(4-1H,4H,5H-pyrazolo[3,4- hydroxypiperidin-4- d]pyrimidin-4-one and tert-yl)ethyl)-1H-pyrazolo[3,4- butyl 2-methyl-1-oxa-6- d]pyrimidin-azaspiro[2.5]octane-6- 4 (5H)-one, TFA salt carboxylate

Example 44: Intermediate 2-878a.6-[(4-Fluorophenyl)carbonyl]-2-methyl-1-oxa-6-azaspiro[2.5]octane

Step 1. 1-(4-Fluorobenzoyl)piperidin-4-one

The title compound was prepared according to procedure described inExample 7 utilizing the piperidin-4-one, TFA salt (1 g, 4.69 mmol) and4-fluorobenzoic acid (1.44 g, 10.3 mmol followed by purification bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:1,v/v) (800 mg, 77%). LCMS: (ESI) m/z 222 [M+H].

Step 2. (4-Ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone

The title compound was prepared according to the procedure outlined inExample 43, Step 1, utilizing 1-(4-fluorobenzoyl)piperidin-4-one (Step1, 800 mg, 3.62 mmol) as starting material which was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:3, v/v)(250 mg, 30%). LCMS: (ESI) m/z 234 [M+H].

Step 3.6-[(4-Fluorophenyl)carbonyl]-2-methyl-1-oxa-6-azaspiro[2.5]octane

The title compound was prepared according to the procedure outlined inExample 43, Step 2, utilizing(4-ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone (Step 2, 250 mg,1.07 mmol) as starting material (250 mg, 93%). LCMS: (ESI) m/z 250[M+H].

Example 45. Intermediate 2-88.4-((1-(4-Fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carbonyl chloride

Triphosgene (0.078 g, 0.263 mmol), triethylamine (0.092 mL, 0.658 mmol),and THF (1.0 mL) were added to a 10-mL round bottom flask fitted with anitrogen inlet and magnetic stir bar. The mixture was cooled to −45° C.,and a solution of1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onehydrochloride (Intermediate 2-86, 0.05 g, 0.132 mmol) in THF (1.0 mL)was added slowly while maintaining the temperature below −35° C. Themixture was stirred for 1 h cold, warmed to room temperature, and thenconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography using dichloromethane-ethyl acetate (1:1 v/v)to give4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carbonylchloride (Intermediate 2-88, 40 mg, 75%). LCMS: (ESI) m/z 406.09 [M+H].

Example 46: Intermediate 91. 1-methyl-4-nitro-1H-pyrazole

A 250-mL round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and thermometer was charged with 4-nitro-1H-pyrazole (5 g, 44.22mmol) and acetonitrile (120 mL) and sodium hydride (2.1 g, 87.50 mmol,60% wt) at −5° C. To the reaction was added iodomethane (7.5 g, 52.8mmol). The product was stirred for 16 h at 23° C. and quenched withwater (20 mL). The product was extracted with ethyl acetate (5×40 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:5v/v) to afford 1-methyl-4-nitro-1H-pyrazole (Intermediate 2-91, 5.2 g,93%). LCMS: (ESI) m/z 128 [M 1H].

Example 47: Intermediate 2-92. 1-phenyl-4-nitro-1H-pyrazole

A 250-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar and thermometer was charged with 4-nitro-1H-pyrazole(4 g, 35.37 mmol), iodobenzene (8 g, 39.2 mmol), copper (I) iodide (2.44g, 12.8 mmol), potassium carbonate (9.66 g, 69.9 mmol) andN,N-dimethylformamide (100 mL). The resulting solution was stirred for12 h at 110° C. and cooled to 23° C. The reaction was quenched withwater (80 mL). The product was extracted with ethyl acetate (3×100 mL).The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (2:3 v/v) toafford of 4-nitro-1-phenyl-1H-pyrazole (Intermediate 2-92, 2.2 g, 33%).LCMS: (ESI) m/z 190 [M+H].

The Intermediate in Table 25 below was synthesized according to theprocedures outlined in Example 47.

TABLE 25 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-331a. 1- 4-nitro-1H-pyrazole 358cyclopropyl-4-nitro-1H-pyrazole

Example 46. Intermediate 2-96.1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid

Step 1. Methyl 4,5,6,7-tetrahydro-11H-indazole-6-carboxylate

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid (640 mg, 3.96mmol), methanol (10 mL) and thionyl chloride (1.43 g, 12.0 mmol). Theresulting solution was stirred for 2 h at 23° C. The reaction mixturewas concentrated under vacuum to afford methyl4,5,6,7-tetrahydro-1H-indazole-6-carboxylate as a yellow oil (645 mg,90%). LCMS: (ESI) m/z 181 [M+H].

Step 2. Methyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith methyl 4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (Step 1, 360mg, 2.00 mmol) and tetrahydrofuran (5 mL, 61.7 mmol). Sodium hydride(120 mg, 3.00 mmol, 60% wt) was added in one portion. The reactionmixture was stirred for 2 h at 23° C. before adding iodomethane (340 mg,2.40 mmol) dropwise. The resulting solution was stirred for 2 h at 23°C. and quenched with water (20 mL). The product was extracted with ethylacetate (3×30 mL). The organic layers were combined, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:10, v/v) to afford methyl1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate as a yellow oil(340 mg, 88%). LCMS: (ESI) m/z 195 [M+H].

Step 3. 1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid

The title compound was prepared according to the procedure outline inExample 10, Step 2 utilizing methyl1-methyl-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (Step 2, 194 mg,1.00 mmol), as starting material (Intermediate 2-96,180 mg, >95%). LCMS:(ESI) m/z 181 [M+H].

Example 47: Intermediate 2-97.4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylic acid

Step 1. Ethyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar, condenser and thermometer was charged with ethyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (500mg, 1.78 mmol), Pd(PPh₃)₄(206 mg, 0.18 mmol), potassium phosphate (1.13g, 5.34 mmol), water (4 mL), 4-bromo-1-methyl-1H-pyrazole (431 mg, 2.68mmol) and 1.4-dioxane (40 mL). The solution was stirred 12 h at 100° C.under nitrogen. The reaction mixture was cooled to 25° C. and dilutedwith water (40 mL). The product was extracted with dichloromethane (3×20mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:10, v/v) to afford ethyl4-(1-methyl-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (0.35 g, 84%).LCMS: (ESI) m/z 235 [M+H].

Step 2. Methyl 4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylate

A 100-mL round-bottom flask fitted with a hydrogen balloon, magneticstir bar was charged with methyl4-(1-methyl-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (Step 1, 300mg, 1.36 mmol), palladium on carbon (50 mg, 10% wt) and methanol (20mL). The mixture was stirred 12 h at 25° C. under hydrogen. The solidswere removed by filtration and the filtrate was concentrated undervacuum to afford methyl4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (0.21 g, 74%).LCMS: (EST) m/z 237 [M+H].

Step 3. 4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 10, Step 2, utilizing methyl4-(1-methyl-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (Step 2, 200 mg,0.90 mmol) as starting material (Intermediate 2-97, 150 mg, 80%). LCMS:(ESI) m/z 209 [M+H].

Example 48: Intermediate 2-114.1-(4-Fluorophenyl)-5-((4-hydroxy-1-(4-oxocyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

The title compound was prepared according to procedure outlined inExample 6 utilizing1-(4-fluorophenyl)-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneTFA salt (Intermediate 2-28, 1.0 g, 2.19 mmol) and4-oxocyclohexane-1-carboxylic acid (prepared according to procedureoutline in Example 8, Step 2, utilizing ethyl4-oxocyclohexane-1-carboxylate as starting material, 625 mg, 4.40 mmol),1.0 g, 49%). LCMS: (ESI) m/z 468 [M+H].

The Intermediates in Table 26 were synthesized according to theprocedure for Example 48 above.

TABLE 26 LCMS: (ES) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-917aa. 5-((4-hydroxy-5-((4-hydroxypiperidin-4-yl)methyl)-1- 4501-(4-oxocyclohexanecarbonyl)piperidin-phenyl-1,5-dihydro-4H-pyrazolo[3,4-4-yl)methyl)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin-4-one, TFA salt and4- d]pyrimidin-4(5H)-one oxocyclohexane-1-carboxylic acid Intermediate2-920aa. 7-(4- 7-(4-fluorophenyl)-3-((4- 467fluorophenyl)-3-((4-hydroxy-1-(4- hydroxypiperidin-4-yl)methyl)-3,7-oxocyclohexane-1-carbonyl)piperidin-4-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3- one TFA salt and4-oxocyclohexane-1- d]pyrimidin-4-one carboxylic acid

Example 49: Intermediate 2-116. 2-cyclopropyl-1,3-oxazole-5-carboxylicacid

Step 1. ethyl 2-cyclopropyl-1,3-oxazole-5-carboxylate

A 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was charged with ethyl2-bromo-1,3-oxazole-5-carboxylate (600 mg, 2.73 mmol),cyclopropylboronic acid (377 mg, 4.39 mmol), toluene (30 mL, 282 mmol),potassium phosphate (1.59 g, 7.49 mmol) in water (4 mL) and 1,1′-(diphenyl phosphine) ferrocene methylene chloride palladiumdichloride (12 mg, 0.06 mmol). The solution was stirred for 16 h at 120°C. in an oil bath. The reaction quenched with water (10 mL) and theproduct was extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtrated andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:20 to 1:5v/v) to give ethyl 2-cyclopropyl-1,3-oxazole-5-carboxylate (70 mg, 61%).LCMS (ES) m/z 182 [M+H].

Step 2. 2-cyclopropyl-1,3-oxazole-5-carboxylic acid

Title compound (400 mg, 86%) was prepared according to the proceduredescribed in Example 10, Step 2, utilizing ethyl2-cyclopropyl-1,3-oxazole-5-carboxylate (Step 1, 550 mg, 3.04 mmol) asstarting material (400 mg, 86%). LCMS: (ES) m/z 154 [M+H].

Example 50: Intermediate 2-119. 1-Cyclopropyl-1H-imidazole-4-carboxylicacid

Step 1. Ethyl 1-cyclopropyl-1H-imidazole-4-carboxylate

A 250-mL round-bottom flask was charged with ethyl1H-imidazole-4-carboxylate (500 mg, 3.57 mmol), cyclopropylboronic acid(614.7 mg, 7.16 mmol), sodium carbonate (757 mg, 7.14 mmol),1,2-dichloroethane (30 mL), 4,4′-bipyridine (558 mg, 3.58 mmol) andcupric acetate (646 mg, 3.56 mmol). The resulting mixture was stirredfor 16 h at 70° C. and cooled to 23° C. The solids were removed byfiltration and the filtrate was concentrated under vacuum. The residuewas purified by column chromatography eluting with ethylacetate/petroleum ether (1:1 v/v) to afford ethyl1-cyclopropyl-1H-imidazole-4-carboxylate (300 mg, 47%). LCMS: (ESI) m/z181 [M+H].

Step 2. 1-Cyclopropyl-1H-imidazole-4-carboxylic acid

Title compound (60 mg, 89%) was prepared according to the proceduredescribed in Example 37, Step 2, utilizing ethyl1-cyclopropyl-1H-imidazole-4-carboxylate (Step 1, 80 mg, 0.44 mmol) asstarting material and used next without further purification. LCMS (ESI)m/z 153 [M+H].

The Intermediate in Table 27 below was also synthesized according to theprocedures outlined for Example 50.

TABLE 27 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-120A & methyl 1H-pyrazole-3- 153 2-120B. carboxylate and1-cyclopropyl-1H-pyrazole- cyclopropylboronic acid 3-carboxylic acid and1-cyclopropyl-1H-pyrazole- 5-carboxylic acid Intermediate 2-121. methyl1H-pyrazole-4- 153 1-Cyclopropyl- carboxylate and1H-pyrazole-4-carboxylic acid cyclopropylboronic acid

Example 51: Intermediate 2-124. 4-Benzyloxazole-5-carboxylic acid

Step 1. Methyl 2-chloro-3-oxo-4-phenylbutanoate

A 250-mL round-bottom flask was charged with methyl3-oxo-4-phenylbutanoate (1.92 g, 9.99 mmol), sulfuryl dichloride (1.62g, 12.0 mmol) and dichloromethane (50 mL). The resulting solution wasstirred for 1 h at 23° C. and then quenched with water (50 mL). Theproduct was extracted with dichloromethane (2×100 mL). The combinedorganic layers were washed with brine (50 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:100 to 1:30 v/v) to afford methyl2-chloro-3-oxo-4-phenylbutanoate (1.65 g, 73%) as a yellow solid. LCMS:(ESI) m/z 227 [M+H].

Step 2. Methyl 4-benzyloxazole-5-carboxylate

A 250-mL round-bottom flask was charged with methyl2-chloro-3-oxo-4-phenylbutanoate (Step 1, 2.26 g, 9.97 mmol), formicacid (30 mL) and ammonium formate (2.31 g, 30.00 mmol). The resultingsolution was stirred for 3 h at 100° C. The reaction was cooled to 23°C. and quenched with saturated sodium bicarbonate (50 mL). The productwas extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:50to 1:8 v/v) to afford methyl 4-benzyloxazole-5-carboxylate (300 mg, 14%)as a yellow solid. LCMS: (ESI) m/z 218 [M+H].

Step 3. 4-Benzyloxazole-5-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 8, Step 2, utilizing methyl 4-benzyloxazole-5-carboxylate (Step2, 300 mg, 1.38 mmol) as starting material (Intermediate 2-124, 245 mg,87%). LCMS: (ESI) m/z 204 [M+H].

Example 52: Intermediate 2-125. 4-(1-methylpyrrolidin-3-yloxy)benzoicacid

Step 1. ethyl 4-(1-methylpyrrolidin-3-yloxy)benzoate

A 100-mL round-bottom flask with a nitrogen ball was charged withpiperidin-4-ol (1 g, 9.89 mmol), triphenylphosphine (3.5 g, 13.34 mmol),ethyl 4-hydroxybenzoate (2.25 g, 13.5 mmol), tetrahydrofuran (50 mL) anddiethyl azodicarboxylate (3.45 g, 19.8 mmol). The resulting solution wasstirred 16 h at 23° C. and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:1 v/v) to afford ethyl 4-(1-methylpyrrolidin-3-yloxy)benzoate(0.5 g, 20%). LCMS: (ESI) m/z 250 [M+H].

Step 2. 4-(1-methylpyrrolidin-3-yloxy)benzoic acid

The title compound was prepared according to the procedure outlined inExample 10, Step 2, utilizing ethyl4-(1-methylpyrrolidin-3-yloxy)benzoate (Step 1, 200 mg, 0.80 mmol) asstarting material (Intermediate 2-125, 0.15 g, 84%) as a yellow oil usedwithout further purification. LCMS: (ESI) m/z 222 [M+H].

The Intermediates in Table 28 below were synthesized according to theprocedures outlined for Example 52.

TABLE 28 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-477a. tert-butyl 4- 322 4-(1-(tert- hydroxypiperidine-1-butoxycarbonyl)piperidin-4- carboxylate and ethyl 4- yloxy)benzoic acidhydroxybenzoate Intermediate 2-126. 4-(1- 1-methylpiperidin-4-ol and 153methylpiperidin-4- ethyl 4-hydroxybenzoate yloxy)benzoic acid

Example 53: Intermediate 2-136. 4-(N-methylsulfamoyl)benzoic acid

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith triethylamine (1 mL), dichloromethane (10 mL) and methanaminehydrochloride (362 mg, 5.40 mmol) and 4-(chlorosulfonyl)benzoic acid(400 mg, 1.81 mmol) in dichloromethane (5 mL) added in portions at 25°C. The resulting solution was stirred for 4 h at 25° C. The reactionmixture was quenched with water (20 mL). The product was extracted withethyl acetate (3×30 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparative thin layer chromatography elutingwith dichloromethane/methanol (20:1, v/v) to afford4-(methylsulfamoyl)benzoic acid as a light yellow solid (Intermediate2-136, 214 mg, 55%). LCMS: (ESI) m/z 216 [M+H].

Example 54: Intermediate 2-140.3-benzyl-1-methyl-1H-pyrazole-4-carboxylic acid

Step 1. Methyl 3-benzyl-1-methyl-11H-pyrazole-4-carboxylate

A 100-mL round-bottom flask flushed with nitrogen was charged withmethyl 3-(bromomethyl)-1-methyl-1H-pyrazole-4-carboxylate (600 mg, 2.60mmol), Pd(dppf)₂Cl₂CH₂Cl₂ (200 mg, 0.27 mmol), potassium carbonate (674mg, 4.88 mmol), 1,4-dioxane (40 mL), water (4 mL) and phenylboronic acid(600 mg, 4.88 mmol). The resulting solution was stirred for 16 h at 100°C. under nitrogen. After cooling to 25° C., the reaction was quenchedwith water (20 mL) and the product was extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine (3×20 mL),dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:1, v/v) to afford methyl3-benzyl-1-methyl-1H-pyrazole-4-carboxylate (150 mg, 26%). LCMS: (ES)m/z 231 [M+H].

Step 2. 3-Benzyl-1-methyl-1H-pyrazole-4-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 10, Step 2, utilizing—methyl3-benzyl-1-methyl-1H-pyrazole-4-carboxylate (Step 1, 150 mg, 0.65mmol),—as starting material (Intermediate 2-140, 160 mg, >95%). LCMS:(ES) m/z 217 [M+H].

Example 55: Intermediate 2-141.1-Methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid

Step 1. 1-(1H-imidazol-1-yl)-2-phenylpropan-1-one

A 500-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 2-phenylpropanoic acid (15 g, 100 mmol), acetonitrile (200 mL) and1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (16.2 g, 99.9 mmol). Theresulting solution was stirred for 2 h at 25° C. The mixture wasconcentrated under vacuum and the residue was diluted with water (50mL). The product was extracted with dichloromethane (3×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum to give1-(1H-imidazol-1-yl)-2-phenylpropan-1-one (28 g, >95%). LCMS: (ES) m-z201 [M+H].

Step 2. Ethyl 3-oxo-4-phenylpentanoate

A 1-L round-bottom flask fitted with a magnetic stir bar was chargedwith 1-ethyl 3-potassium propanedioate (35 g, 206 mmol), acetonitrile(500 mL), triethylamine (31 g, 306 mmol), magnesium chloride (24 g, 252mmol) and 1-(1H-imidazol-1-yl)-2-phenylpropan-1-one (Step 1, 20 g, 100mmol). The resulting solution was stirred for 10 h at 25° C. The mixturewas concentrated under vacuum. The residue was diluted with water (100mL) and the product was extracted with dichloromethane (3×100 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:1,v/v) to give ethyl 3-oxo-4-phenylpentanoate (20 g, 91%). LCMS: (ES) m/z221 [M+H].

Step 3. Ethyl-2-[(dimethylamino)methylidene]-3-oxo-4-phenylpentanoate

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with ethyl3-oxo-4-phenylpentanoate (Step 2, 1 g, 4.54 mmol) andN,N-dimethylformamide dimethyl acetal (30 mL). The resulting solutionwas stirred for 1 h at 110° C. After cooling to 25° C., the mixture wasconcentrated under vacuum to giveethyl-2-[(dimethylamino)methylidene]-3-oxo-4-phenylpentanoate as ayellow oil (1 g, 80%). LCMS: (ES) m/z 276 [M+H].

Step 4. Ethyl 1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylate

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith ethyl-2-[(dimethylamino)methylidene]-3-oxo-4-phenylpentanoate (Step3, 550 mg, 2.00 mmol), ethanol (20 mL), a solution of methylhydrazine inwater (10 mL, 40%) and triethylamine (606 mg, 5.99 mmol). The resultingsolution was stirred for 3 h at 25° C. The solvent was removed undervacuum and the residue was diluted with water (20 mL). The product wasextracted with ethyl acetate (3×30 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography eluting withethyl acetate/petroleum ether (1:1, v/v) to give ethyl1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylate (340 mg, 66%).LCMS: (ES) m/z 259 [M+H].

Step 5. 1-Methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid

The title compound was prepared according to the procedure outline dinExample 10, Step 2, utilizing ethyl1-methyl-3-(1-phenylethyl)-1H-pyrazole-4-carboxylate (Step 4, 340 mg,1.32 mmol) as starting material (Intermediate 2-141, 300 mg, >95%).LCMS: (ES) m/z 231 [M+H].

Example 56: Intermediate 2-144.3-benzyl-5-methyl-1,2-oxazole-4-carboxylic acid

Step 1. Methyl (2E)-2-acetyl-3-amino-4-phenylbut-2-enoate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with methyl 3-oxobutanoate (3.24mL, 27.9 mmol), SnCl₄ in dichloromethane (3.5 mL, 3.50 mmol, 1 M),toluene (40 mL) and 2-phenylacetonitrile (3.46 mL). The resultingsolution was stirred for 2 h at 110° C. After cooling to 25° C., thesolids were removed by filtration. The filtrate was diluted with water(20 mL). The resulting mixture was extracted with dichloromethane (3×20mL). The combined organic layers were washed with saturated ammoniumbicarbonate (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:10, v/v) toafford methyl (2E)-2-acetyl-3-amino-4-phenylbut-2-enoate as a yellow oil(3.2 g, 49%). LCMS: (ES) m/z 234 [M+H].

Step 2. Methyl 3-benzyl-5-methyl-1,2-oxazole-4-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with triethylamine (0.75 mL),ethanol (15 mL) and hydroxylamine (375 mg, 11.35 mmol). The mixture wasstirred for 1 h at 25° C. before adding methyl(2E)-2-acetyl-3-amino-4-phenylbut-2-enoate (Step 1, 1.05 g, 4.50 mmol).The reaction was heated to 100° C. and stirred for 5 h. After cooling to25° C., the resulting mixture was concentrated under vacuum. The residuewas purified by column chromatography eluting with ethylacetate/petroleum ether (1:5, v/v) to afford methyl3-benzyl-5-methyl-1,2-oxazole-4-carboxylate as a yellow oil (800 mg,77%). LCMS: (ES) m/z 232 [M+H].

Step 3. 3-benzyl-5-methyl-1,2-oxazole-4-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 14, utilizing methyl 3-benzyl-5-methyl-1,2-oxazole-4-carboxylate(Step 2, 300 mg, 1.30 mmol) as starting material, (Intermediate 2-144,0.15 g, 53%). LCMS: (ES) m/z 218 [M+H].

Example 57: Intermediate 2-147. 1-methyl-4-(1H-pyrazol-4-yl)piperazineHydrochloride salt

Step 1. 1-Methyl-4-(1-trityl-1H-pyrazol-4-yl)piperazine

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with4-bromo-1-(triphenylmethyl)-1H-pyrazole (1 g, 2.57 mmol),1-methylpiperazine (516 mg, 5.15 mmol), sodium tert-butoxide (743 mg,7.73 mmol), toluene (30 mL),tris(dibenzylideneacetone)dipalladium-chloroform adduct (207 mg, 0.20mmol) and X-Phos (123 mg, 0.26 mmol). The solution was stirred for 16 hat 120° C. in an oil bath. After cooling to 25° C., the reaction wasquenched with water (30 mL). The product was extracted with ethylacetate (3×30 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with dichloromethane/methanol(10:1, v/v) to afford1-methyl-4-[1-(triphenylmethyl)-1H-pyrazol-4-yl]piperazine as a brownsolid (200 mg, 19%). LCMS: (ESI) m/z 409 [M+H].

Step 2. 1-methyl-4-(1H-pyrazol-4-yl)piperazine Hydrochloride salt

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 1-methyl-4-[1-(triphenylmethyl)-1H-pyrazol-4-yl]piperazine (Step 1,200 mg, 0.49 mmol) and hydrogen chloride in 1,4-dioxane (15 mL, 3M). Thesolution was stirred for 2 h at 25° C. and concentrated under vacuum.The residue was diluted with ethyl acetate (20 mL). The solids werecollected by filtration, washed with ethyl acetate (10 mL) and dried inan oven to afford the 1-methyl-4-(1H-pyrazol-4-yl)piperazine, HCl salt(Intermediate 2-147, 250 mg). LCMS: (ESI) m/z 167[M+H]

Example 58: Intermediate 2-148. 2H,4H,6H,7H-pyrano[4,3-c]pyrazole

Step 1. (Z)-3-((dimethylamino)methylene)-tetrahydropyran-4-one

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with oxan-4-one (1 g, 9.99 mmol),DMF-DMA (30 mL). The solution was stirred for 3 h at 110° C. Thereaction mixture was cooled to 25° C. and concentrated under vacuum toafford (Z)-3-((dimethylamino)methylene)tetrahydro-4H-pyran-4-one (600mg, 39%). LCMS: (ESI) m/z 156 [M+H].

Step 2. 2H,4H,6H,7H-pyrano[4,3-c]pyrazole

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with(Z)-3-((dimethylamino)methylene)tetrahydro-4H-pyran-4-one (Step 1, 600mg, 3.87 mmol), hydrazine (1 mL) and ethanol (20 mL). The solution wasstirred for 5 h at 90° C. and cooled to 25° C. The solution wasconcentrated under vacuum and purified by column chromatography elutingwith dichloromethane/methanol (30:1, v/v) to afford2H,4H,6H,7H-pyrano[4,3-c]pyrazole as a white solid (Intermediate 2-148,300 mg, 63%). LCMS: (ESI) m/z 125 [M+H].

Example 59: Intermediate 2-149.5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 250-mL 3-necked round-bottom flask was fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with1-(4-bromophenyl)-5-((1-(cyclopropane-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(2.5 g, 5.29 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2 g, 7.88 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane complex (217 mg, 0.27mmol), potassium acetate (1.56 g, 15.90 mmol) and N,N-dimethylformamide(50 mL). The resulting solution was stirred for 5 h at 90° C. undernitrogen. After cooling to 23° C., the reaction was with water (200 mL).The product was extracted with ethyl acetate (4×200 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The solids were collected by filtration,washed with methanol (100 mL) and dried in an oven to afford5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Intermediate 2-149, 1.80 g, 65%). ¹H-NMR (400 MHz, DMSO-d₆) δ 0.65-0.75(m, 4H), 1.32 (s, 12H), 1.35-1.65 (m, 4H), 1.92-2.00 (m, 1H), 2.92-3.01(m, 1H), 3.34-3.45 (m, 1H), 3.95-4.15 (m, 4H), 4.97 (s, 1H), 7.86 (d,J=8.4 Hz, 2H), 8.17 (d, J=8.4 Hz, 2H), 8.39 (s, 1H), 8.40 (s, 1H). LCMS:(ESI) m/z 520 [M+H].

Example 60: Intermediate 2-152.4-((1-(3-bromophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide

A 250-mL round-bottom flask was charged with the TFA salt of1-(3-bromophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(4.40 g, 9.98 mmol), dichloromethane (100 mL) and DIPEA (3.87 g, 29.94mmol). This was followed by the addition of a solution ofN,N-dimethylcarbamoyl chloride (1.28 g, 11.90 mmol) in dichloromethane(30 mL) at 0° C. After addition, the resulting solution was stirred for1 h at 0° C. The reaction was then quenched by the addition of 50 mL ofwater. The resulting mixture was extracted with dichloromethane (3×100mL) and the organic layers combined, washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography eluting withdichloromethane/methanol (20:1, v/v) to afford4-((1-(3-bromophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide(Intermediate 2-152, 3.28 g, 69%). ¹H-NMR (400 MHz, DMSO-d₆) δ 1.36-1.39(m, 2H), 1.54-1.61 (m, 2H), 2.72 (s, 6H), 2.95-3.01 (m, 2H), 3.27-3.32(m, 2H), 4.04 (s, 2H), 4.88 (brs, 1H), 7.53-7.57 (m, 1H), 7.60-7.63 (m,1H), 8.12-8.15 (m, 1H), 8.34 (t, J=2.4 Hz, 1H), 8.40 (s, 1H), 8.41 (s,1H). LCMS: (ESI) m/z 475, 477 [M+H].

Table 29: The Intermediates in Table 29 were prepared according to theprocedure outlined in Example 60.

TABLE 29 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-828a. 1-(3-bromo-4-fluorophenyl)- 493 4-[[1-(3-bromo-4-5-((4-hydroxypiperidin-4- fluorophenyl)-4-oxo-yl)methyl)-1,5-dihydro-4H- 1H,4H,5H-pyrazolo[3,4-pyrazolo[3,4-d]pyrimidin-4- d]pyrimidin-5- one, TFA salt yl]methyl]-4-hydroxy-N,N- dimethylpiperidine-1- carboxamide

Example 61: Intermediate 2-103a. Methyl4-hydroxy-1-methylcyclohexanecarboxylate

Step 1. Methyl 4-hydroxy-1-methylcyclohexanecarboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar andthermometer was charged with methyl1-methyl-4-oxocyclohexane-1-carboxylate (552 mg, 3.24 mmol) and methanol(20 mL). Then sodium borohydride (226 mg, 5.97 mmol) was added at 0° C.The resulting solution was stirred for 3 h at 0° C. and concentratedunder vacuum. The solids were filtered and washed with ethyl acetate(3×50 mL). The filtrate was concentrated under vacuum to afford methyl4-hydroxy-1-methylcyclohexane-1-carboxylate (400 mg, 68%). LCMS: (ESI)m/z 173 [M+H].

Example 62: Intermediate 2-67. 5-(Pyridin-2-yloxy)picolinic acid

Step 1. Ethyl 4-(pyridin-2-yloxy)cyclohexane-1-carboxylate

A 100-mL 3-necked round-bottom flask equipped with a nitrogen balloonwas charged with ethyl 4-hydroxycyclohexane-1-carboxylate (1.81 g, 10.51mmol), pyridin-2-ol (500 mg, 5.26 mmol), triphenylphosphine (2.76 g,10.52 mmol) and tetrahydrofuran (20 mL). A solution of diethylazodicarboxylate (1.83 g, 10.51 mmol) in tetrahydrofuran (5 mL) wasadded at 0° C. The resulting solution was stirred 16 h at 23° C. andthen concentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:30 to 1:10v/v) to afford ethyl 4-(pyridin-2-yloxy)cyclohexane-1-carboxylate (600mg, 46%). LCMS: (ESI) m/z 250 [M+H].

Step 2. 4-(Pyridin-2-yloxy)cyclohexane-1-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 10, Step 2, utilizing ethyl4-(pyridin-2-yloxy)cyclohexane-1-carboxylate (Step 1, 600 mg, 2.41mmol), as starting material (Intermediate 2-67, 450 mg, 85%). LCMS (ESI)m/z 222 [M+H].

The Intermediates in Table 30 below were synthesized according to theprocedures outlined above.

TABLE 30 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H]Intermediate 2-103. 1-methyl-4-(pyridin-2- pyridin-2-ol and methyl 4-236 yloxy) cyclohexanecarboxylic acid hydroxy-1-methylcyclohexane-1-carboxylate (Intermediate 2- 103a) Intermediate 2-104.4-[(5-fluoropyridin-2- 5-fluoropyridin-2-ol and ethyl 4- 240yl)oxy]cyclohexane-1-carboxylic acid hydroxycyclohexane-1- carboxylateIntermediate 2-105. 4-(6-fluoropyridin-2- 6-fluoropyridin-2-ol ethyl 4-240 yloxy) cyclohexanecarboxylic acid hydroxycyclohexane-1- carboxylateIntermediate 2-106. 4-(pyridin-3-yloxy) 3-hydroxypyridine and ethyl 4-222 cyclohexanecarboxylic acid hydroxycyclohexane-1- carboxylateIntermediate 2-113. (1r,4r)-4-(Pyridin-2- cis-4-hydroxycyclohexane-1-222 yloxy) cyclohexanecarboxylic acid carboxylate and pyridin-2-olIntermediate 2-128. (1s,3s)-3-(pyridin-2- methyl (1r,3r)-3- 194yloxy)cyclobutane-1-carboxylic acid hydroxycyclobutane-1- carboxylateand pyridin-2-ol Intermediate 2-4000. (1r,4r)-4-((2-cis-4-hydroxycyclohexane-1- 237 methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate and 2-methyl-4- carboxylic acid hydroxypyrimidine

Example 63: Intermediate 2-68. 5-(Pyridin-2-yloxy)picolinic acid

Step 1. Methyl 5-(pyridin-2-yloxy)picolinate

A 50-mL round-bottom flask was charged with methyl5-hydroxypyridine-2-carboxylate (306 mg, 2.00 mmol), potassium carbonate(552 mg, 3.99 mmol) and 2-bromopyridine (632 mg, 4.00 mmol) in DMF (10mL). The resulting solution was stirred for 3 h at 150° C. and cooled to23° C. The reaction was quenched with water (20 mL) and the product wasextracted with dichloromethane (3×10 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by preparative thin layerchromatography eluting with 1/30-1/4 ethyl acetate/petroleum ether (1:30to 1:4 v/v) to afford methyl 5-(pyridin-2-yloxy)picolinate (320 mg,70%). LCMS: (ESI) m/z 231 [M+H].

Step 2. 5-(Pyridin-2-yloxy)picolinic acid

The title compound was prepared according to the procedure outlined inExample 8, Step 2, utilizing methyl 5-(pyridin-2-yloxy)picolinate (Step1, 230 mg, 1.00 mmol) as starting material (Intermediate 2-68, 180 mg,83%). LCMS: (ESI) m/z 217 [M+H].

The compounds below were also synthesized according to the proceduresoutlined above.

TABLE 31 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H]Intermediate 2-69. 4-(Pyridin-2- 4-hydroxybenzoic acid and 2- 216yloxy)benzoic acid chloropyridine Intermediate 2-70. 4-(pyrimidin-2-4-hydroxybenzoic acid and 2- 217 yloxy)benzoic acid bromopyrimidineIntermediate 2-169. (1r,4r)-4-((5- cis-4-hydroxycyclohexane-1- 247cyanopyridin-2-yl)oxy)cyclohexane-1- carboxylate and 6- carboxylic acidchloronicotinonitrile Intermediate 2-170. (1r,4r)-4-((6-cis-4-hydroxycyclohexane-1- 237 methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate and 2-chloro-6- carboxylic acid methylpyrazine Intermediate2-171. (1r,4r)-4-((2- cis-4-hydroxycyclohexane-1- 237methylpyrimidin-4-yl)oxy)cyclohexane-1- carboxylate and 4-chloro-2-carboxylic acid methylpyrimidine Intermediate 2-82. 4-(1-methyl-1H-4-hydroxybenzoic acid and 4- 219 pyrazol-4-yloxy)benzoic acidchloro-1-methyl-1H-pyrazole Intermediate 2-118. 2-(Pyridin-2-2-chloro-1,3-oxazole-5-carboxylate 207 yloxy)oxazole-5-carboxylic acidand pyridin-2-ol

Example 64: Intermediate 2-102.4-(Pyrimidin-2-yloxy)cyclohexanecarboxylate acid

Step 1. Ethyl 4-(pyrimidin-2-yloxy)cyclohexanecarboxylate

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with ethyl4-hydroxycyclohexane-1-carboxylate (1 g, 5.81 mmol), CuI (111 mg, 0.58mmol), Cs₂CO₃ (3.79 g, 11.6 mmol), toluene (25 mL), 2-chloropyrimidine(665 mg, 5.81 mmol), 1,10-phenanthroline (209 mg, 1.16 mmol). Theresulting solution was stirred for 24 h at 120° C. in an oil bath. Theresulting solution was cooled to 20° C. and quenched with water (50 mL).The product was extracted with ethyl acetate (5×50 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/hexane (1:4, v/v) to affordethyl 4-(pyrimidin-2-yloxy)cyclohexane-1-carboxylate (0.356 g, 24%).LCMS: (ESI) m/z 251 [M+H].

Step 2. 4-(Pyrimidin-2-yloxy)cyclohexanecarboxylic acid

The title compound was prepared according to procedure outlined inExample 10, Step 2, utilizing ethyl4-(pyrimidin-2-yloxy)cyclohexane-1-carboxylate (Step 1, 356 mg, 1.42mmol) as starting material (Intermediate 2-102, (222 mg 70%) LCMS: (ESI)m/z 223 [M+H].

Example 65: Intermediate 2-145.4-(5-(2-Hydroxyethoxy)pyridin-2-yloxy)benzoic acid

Step 1. Ethyl 4-(5-methoxypyridin-2-yloxy)benzoate

A 50-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with ethyl4-hydroxybenzoate (1.66 g, 9.99 mmol), DMSO (20 mL), CuI (95 mg, 0.50mmol), picolinic acid (123 mg, 1.00 mmol), K₃PO₄ (4.24 g, 19.97 mmol)and 2-bromo-5-methoxypyridine (1.88 g, 10.0 mmol). The resultingsolution was stirred for 16 h at 90° C. After cooling to 25° C., thereaction was quenched with water (50 mL). The product was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with dichloromethane/methanol (10:1, v/v) toafford ethyl 4-(5-methoxypyridin-2-yloxy)benzoate as a yellow solid(1.20 g, 44%). LCMS: (ESI) m/z 274 [M+H].

Step 2. Ethyl 4-(5-hydroxypyridin-2-yloxy)benzoate

A 25-mL round-bottom flask fitted with a magnetic stir bar was chargedwith ethyl 4-(5-methoxypyridin-2-yloxy)benzoate (Step 1, 320 mg, 1.17mmol), dichloromethane (10 mL) and a solution of BBr₃ in dichloromethane(1.5 mL, 1.5 mmol, 1M). The resulting solution was stirred for 16 h at25° C. The pH was adjusted to 7-8 with saturated sodium bicarbonate. Theresulting mixture was extracted with dichloromethane (3×30 mL). Thecombined organic layers were washed brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by preparative thin layer chromatography eluting with ethylacetate/petroleum ether (2:1, v/v) to afford ethyl4-(5-hydroxypyridin-2-yloxy)benzoate (130 mg, 43%). LCMS: (ESI) m/z 260[M+H]

Step 3. Ethyl 4-(5-(2-hydroxyethoxy)pyridin-2-yloxy)benzoate

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with ethyl4-(5-hydroxypyridin-2-yloxy)benzoate (Step 2, 259 mg, 1.00 mmol),N,N-dimethylformamide (15 mL), cesium carbonate (652 mg, 2.00 mmol) and1,3-dioxolan-2-one (132 mg, 1.50 mmol). The resulting solution wasstirred for 3 h at 80° C. The reaction mixture was cooled to 27° C. Thereaction was quenched with water (25 mL). The product was extracted withdichloromethane (3×25 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparative thin layer chromatography elutingwith ethyl acetate/petroleum ether (5:1, v/v) to afford ethyl4-(5-(2-hydroxyethoxy)pyridin-2-yloxy)benzoate as a yellow solid (242mg, 80%). LCMS: (ESI) m/z 304 [M+H].

Step 4. 4-(5-(2-Hydroxyethoxy)pyridin-2-yloxy)benzoic acid

The title compound was prepared according to the procedure outlined inExample 8, Step 2, utilizing ethyl4-(5-(2-hydroxyethoxy)pyridin-2-yloxy)benzoate (Step 3, 242 mg, 0.80mmol) as starting material (Intermediate 2-145, 180 mg, 82%). LCMS:(ESI) m/z 276 [M+H].

Example 66: Intermediate 2-146. trans-4-(Pyridazin-3-yloxy)cyclohexanecarboxylic acid

Step 1. Trans-methyl 4-(6-chloropyridazin-3-yloxy)cyclohexanecarboxylate

A 5-mL microwave tube fitted with a magnetic stir bar was charged withmethyl trans-4-hydroxycyclohexane-1-carboxylate (200 mg, 1.26 mmol),3,6-dichloropyridazine (188 mg, 1.26 mmol) and N,N-dimethylformamide(2.5 mL) followed by sodium hydride (65.6 mg, 1.64 mmol, 60%) added inportions. The microwave tube was sealed until the bubbling ceased andthe reaction mixture was irradiated with microwave for 30 min at 100° C.After cooling to 25° C., the resulting mixture was poured into water (10mL) The mixture was extracted with ethyl acetate (3×30 mL) and thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bypreparative thin layer chromatography eluting with ethylacetate/petroleum (1:3, v/v) to afford methyltrans-4-[(6-chloropyridazin-3-yl)oxy]cyclohexane-1-carboxylate as anoff-white solid (80 mg, 23%). LCMS: (ESI) m/z 271, 273[M+H].

Step 2. Trans-methyl 4-(pyridazin-3-yloxy)cyclohexanecarboxylate

A 100-mL round-bottom flask fitted with a hydrogen balloon, magneticstir bar was charged with methyltrans-4-[(6-chloropyridazin-3-yl)oxy]cyclohexane-1-carboxylate (Step 1,80 mg, 0.30 mmol), methanol (15 mL), triethanolamine (59.8 mg, 0.59mmol) and palladium on carbon (30 mg, 0.03 mmol, 10%). The solution wasstirred for 2 h at 25° C. under hydrogen. The solids were removed byfiltration. The filtrate was concentrated under vacuum to afford methyltrans-4-(pyridazin-3-yloxy)cyclohexane-1-carboxylate as a colorless oil(60 mg). LCMS: (ESI) m/z 237[M+H].

Step 3. Trans-4-(pyridazin-3-yloxy)cyclohexanecarboxylic acid

The title compound was prepared according to the procedure outlined inExample 8, Step 2, utilizing methyltrans-4-(pyridazin-3-yloxy)cyclohexane-1-carboxylate (Step 2, 60 mg,0.25 mmol) as starting material (Intermediate 2-146, 45 mg). LCMS: (ESI)m/z 223 [M+H].

Example 67: Intermediate 172.trans-4-[[6-(azetidin-1-yl)pyridin-2-yl]oxy]cyclohexane-1-carboxylicacid

Step 1. 2-(azetidin-1-yl)-6-(benzyloxy)pyridine

A 250-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar and thermometer was charged with2-(benzyloxy)-6-bromopyridine (1 g, 3.79 mmol), Pd₂(dba)₃.CHCl₃(400 mg,0.39 mmol), BiNAP (480 mg, 0.77 mmol), potassium tert-butoxide (732 mg,6.52 mmol), toluene (20 mL) and azetidine (440 mg, 7.71 mmol). Theresulting solution was stirred for 6 h at 80° C. After cooling to 25°C., the reaction was quenched with water (20 mL). The product wasextracted with ethyl acetate (4×30 mL) and the organic layers werecombined. The solution was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:5, v/v) toafford 2-(azetidin-1-yl)-6-(benzyloxy)pyridine as light yellow oil (0.6g, 66%). LCMS: (ESI) m/z 241 [M+H].

Step 2. 6-(azetidin-1-yl)pyridin-2-ol

The title compound was prepared according to the procedure outlined inExample 180 utilizing 2-(azetidin-1-yl)-6-(benzyloxy)pyridine (Step 1,500 mg, 2.08 mmol), as starting material (0.35 g, >95%). LCMS: (ESI) m/z151[M+H].

Step 3.Trans-methyl-4-[[6-(azetidin-1-yl)pyridin-2-yl]oxy]cyclohexane-1-carboxylate

The title compound was prepared according to the procedure outlined inExample 66, Step 1, utilizing 6-(azetidin-1-yl)pyridin-2-ol (Step 2, 127mg, 0.85 mmol) andcis-methyl-4-(methanesulfonyloxy)cyclohexane-1-carboxylate (200 mg, 0.85mmol) as starting materials. The title compound was purified bypreparative TLC eluting with ethyl acetate/petroleum ether (1:3, v/v)(60 mg, 24%). LCMS: (ESI) m/z 291 [M+H].

Step 4.Trans-4-[[6-(azetidin-1-yl)pyridin-2-yl]oxy]cyclohexane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 10, Step 2, utilizingtrans-methyl-4-[[6-(azetidin-1-yl)pyridin-2-yl]oxy]cyclohexane-1-carboxylate(Step 3, 60 mg, 0.21 mmol) as starting material (34 mg, 59%). LCMS:(ESI) r/z 277 [M+H].

Example 68: Intermediate 175.cis-4-(pyrazin-2-yloxy)cyclohexanecarboxylic acid

Step 1. Cis-methyl 4-(pyrazin-2-yloxy)cyclohexanecarboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with methyltrans-4-hydroxycyclohexane-1-carboxylate (400 mg, 2.53 mmol),N,N-dimethylformamide (15 mL), 2-chloropyrazine (348 mg, 3.03 mmol),potassium carbonate (1.05 g, 7.60 mmol) and sodium methanesulfinate (387mg, 3.79 mmol). The resulting mixture was stirred for 16 h at 120° C. inan oil bath. After cooling to 25° C., the reaction was quenched withwater (30 mL). The product was extracted with ethyl acetate (3×30 mL)and the combined organic layers dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bypreparative thin layer chromatography eluting with ethylacetate/petroleum (1:4, v/v) to afford methylcis-4-(pyrazin-2-yloxy)cyclohexane-1-carboxylate (80 mg, 13%). LCMS:(ESI) m/z 237[M+H].

Step 2. Cis-4-(pyrazin-2-yloxy)cyclohexanecarboxylic acid

The title compound was prepared according to the procedure outline inExample 8, Step 2, utilizing methylcis-4-(pyrazin-2-yloxy)cyclohexane-1-carboxylate (Step 1, 80 mg, 0.34mmol) as starting material (65 mg, 86%). LCMS: (ESI) m/z 223[M+H].

The Intermediates in Table 32 below were synthesized according to theprocedures outlined above.

TABLE 32 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H]Intermediate 2-132. trans-4- methyl cis-4- 223 (pyrazin-2-hydroxycyclohexane-1- yloxy)cyclohexanecarboxylic carboxylate and acid2-chloropyrazine

Example 69: Intermediate 2-107.4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexane-1-carboxylic

Step 1. Ethyl 4-(methanesulfonyloxy)cyclohexane-1-carboxylate

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar andthermometer was charged with ethyl 4-hydroxycyclohexane-1-carboxylate(1.5 g, 8.71 mmol), triethylamine (2.64 g, 26.09 mmol) anddichloromethane (50 mL). To the reaction was added methanesulfonylchloride (1.49 g, 13.01 mmol) added dropwise with stirring at 0° C. Theresulting solution was stirred for 2 h at 25° C. The resulting solutionwas diluted with water (20 mL) and the product was extracted withdichloromethane (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:5, v/v) to afford ethyl4-(methanesulfonyloxy) cyclohexane-1-carboxylate as a light yellow oil(1.2 g, 55%). LCMS: (ESI) m/z 251 [M+H], 155 [M-OMs].

Step 2. Ethyl 4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexane-1-carboxylate

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with ethyl4-(methanesulfonyloxy)cyclohexane-1-carboxylate (Step 1, 600 mg, 2.40mmol), potassium carbonate (993 mg, 7.18 mmol), N,N-dimethylformamide(10 mL) and 1-methyl-1H-pyrazol-4-ol (353 mg, 3.60 mmol). The resultingsolution was stirred 7 h at 60° C. and cooled to 25° C. The product wasdiluted with water (40 mL) and extracted with dichloromethane (3×50 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by a preparative TLCplate eluting with ethyl acetate/petroleum ether (1:1, v/v) to affordethyl 4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexane-1-carboxylate as ayellow oil (0.42 g, 69%). LCMS: (ESI) m/z 253 [M+H].

Step 3. 4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexane-1-carboxylic

The title compound was prepared according to the procedure outline inExample 8, Step 2, utilizing ethyl4-[(1-methyl-1H-pyrazol-4-yl)oxy]cyclohexane-1-carboxylate (Step 2, 300mg, 1.19 mmol) as starting material (Intermediate 2-107, 0.16 g, 60%).LCMS: (ESI) m/z 225 [M+H].

The Intermediates in Table 33 were synthesized according to theprocedure above for Example 69.

TABLE 33 LCMS: (ES) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-108. 4-(pyridin-4- ethyl 4- 222yloxy)cyclohexane-1-carboxylic acid (methanesulfonyloxy)cyclohexane-1-carboxylate and 4- hydroxypyridine Intermediate 2-109.4-[(1-methyl-1H- ethyl 4- 225 pyrazol-3-yl)oxy]cyclohexane-1-carboxylic(methanesulfonyloxy)cyclohexane- acid 1-carboxylate and 1-methyl-1H-pyrazol-3-ol Intermediate 2-110. 4-[(5-methyl-1,2- ethyl 4- 226oxazol-3-yl)oxy]cyclohexane-1-carboxylic(methanesulfonyloxy)cyclohexane- acid 1-carboxylate and 5-methylisoxazol-3-ol Intermediate 2-174. (1r,4r)-4-((2- (1s,4s)-4- 240fluoropyridin-3-yl)oxy)cyclohexane-1- ((methylsulfonyl)oxy)cyclohexane-carboxylic acid 1-carboxylic acid and 2- fluoropyridin-3-ol Intermediate2-173. 4-[(5- ethyl 4- 252 methoxypyridin-2-yl)oxy]cyclohexane-1-(methanesulfonyloxy)cyclohexane- carboxylic acid 1-carboxylate and 5-methoxypyridin-2-ol Intermediate 2-130. (1r,4r)-4-(1-methyl- (1s,4s)-4-225 1H-pyrazol-5-yloxy)cyclohexane- ((methylsulfonyl)oxy)cyclohexane-carboxylic acid 1-carboxylic acid and 1- methyl-1H-pyrazol-5-ol

Example 70: Intermediate 2-228a. 1,5-dibenzyl-1H-pyrazole-4-carboxylicacid

Step 1. Methyl 2-((dimethylamino)methylene)-3-oxo-4-phenylbutanoate

A 50-mL round-bottom flask was charged with methyl3-oxo-4-phenylbutanoate (1.92 g, 9.99 mmol) and(dimethoxymethyl)dimethylamine (1.43 g, 12.0 mmol). The resultingsolution was stirred for 1 h at 23° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:3, v/v) toafford methyl 2-((dimethylamino)methylene)-3-oxo-4-phenylbutanoate (2.30g, 93%). LCMS: (ESI) m/z 248 [M+H].

Step 2. Methyl 1,5-dibenzyl-1H-pyrazole-4-carboxylate

A 50-mL round-bottom flask was charged with methyl2-((dimethylamino)methylene)-3-oxo-4-phenylbutanoate (Step 1, 850 mg,3.44 mmol), phenylhydrazine (557 mg, 5.15 mmol) and ethanol (25 mL). Theresulting solution was refluxed for 3 h. The resulting mixture wasconcentrated under vacuum. The residue was diluted with water (30 mL)and the product was extracted with ethyl acetate (5×30 mL). The organiclayers were combined, washed with brine (30 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (1:3, v/v) to afford methyl 1,5-dibenzyl-1H-pyrazole-4-carboxylateas a yellow solid (620 mg, 59%). LCMS: (ESI) m/z 307 [M+H].

Step 3. 1,5-dibenzyl-1H-pyrazole-4-carboxylic acid

The title compound was prepared according to the procedure outlined inExample 14 utilizing methyl 1,5-dibenzyl-1H-pyrazole-4-carboxylate (Step2, 620 mg, 2.02 mmol as starting material (472 mg, 80%). LCMS: (ESI) m/z293 [M+H].

Example 71: Intermediate 2-160. 4-(1,1-difluoroethyl)benzoic acid

Step 1. Methyl 4-(1,1-difluoroethyl)benzoate

A 100-mL high pressure reaction tube fitted with a magnetic stir bar,condenser and thermometer was charged with methyl 4-acetylbenzoate (300mg, 1.68 mmol), ethanol (0.02 mL), diethyl(trifluoro-4-sulfanyl)amine(814 mg, 5.05 mmol) and chloroform (20 mL). The resulting solution wassealed and stirred for 10 h at 80° C. After cooling to 23° C., thereaction mixture was poured into a saturated aqueous sodium bicarbonate(30 mL). The product was extracted with dichloromethane (3×30 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (4:1v/v)) to afford methyl 4-(1,1-difluoroethyl)benzoate as a yellow solid(200 mg, 59%). LCMS (ESI) m/z 201 [MI-H].

Step 2. 4-(1,1-Difluoroethyl)benzoic acid

The title compound was prepared according to the procedure outline inExample 10, Step 2, utilizing methyl 4-(1,1-difluoroethyl)benzoate (Step1, 150 mg, 0.75 mmol) as starting material (Intermediate 2-160, 150 mg).LCMS (ESI, m/z 185 [M−H].

Example 72: Intermediate 2-166. 4-(oxan-4-yloxy)cyclohexane-1-carboxylicacid

Step 2. Ethyl 4-[(trimethylsilyl)oxy]cyclohexane-1-carboxylate

A 50-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar and thermometer was charged with ethyl4-[(trimethylsilyl)oxy]cyclohexane-1-carboxylate (Step 1, 200 mg, 0.82mmol), dichloromethane (8 mL) and oxan-4-one (70 mg, 0.70 mmol) followedby trimethylsilyl trifluoromethanesulfonate (18 mg, 0.08 mmol) addeddropwise with stirring at −78° C. over 5 min. Stirring continued for 1 hbefore adding triethylsilane (93 mg, 0.80 mmol) in dichloromethane (1mL) in portions. Following the addition, the reaction was warmed to 23°C. and stirred for 16 h. The reaction was quenched with saturated sodiumbicarbonate (10 mL). The product was extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (2×20 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography eluting with petroleumether/ethyl acetate (10:1, v/v) to afford ethyl4-(oxan-4-yloxy)cyclohexane-1-carboxylate as light yellow oil (120 mg,57%). GCMS: m/z 256.

Step 3. 4-(Oxan-4-yloxy)cyclohexane-1-carboxylic acid

The title compound was prepared according to the procedure outline inExample 10, Step 2, utilizing ethyl4-(oxan-4-yloxy)cyclohexane-1-carboxylate (Step 2, 100 mg, 0.39 mmol) asstarting material (Intermediate 2-166, 50 mg, 56%). LCMS: (ESI) m/z 227[M−H].

Step 1. Methyl 2,4-dibromopentanoate

A 500-mL 3-necked round-bottom with fitted with a magnetic stir bar,condenser and thermometer was charged with 5-methyloxolan-2-one (10 g,100 mmol), methanol (100 mL), hydrochloric acid (20 mL, 12N) andphosphorus tribromide (4.5 mL). Bromine (6 mL) was added in portions at25° C. After addition, the resulting solution was stirred for 30 min at110° C. in an oil bath and cooled to 25° C., the solution was dilutedwith methanol (100 mL) and hydrochloric acid (20 mL, 12 N). Theresulting solution was stirred for 16 h at 25° C. and then concentratedunder vacuum. The residue was diluted with water (100 mL) and theproduct was extracted with ethyl acetate (3×30 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum to afford methyl 2,4-dibromopentanoate as a colorless oil (6 g).

Step 2. Methyl 1-benzyl-4-methylazetidine-2-carboxylate

A 500-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with methyl 2,4-dibromopentanoate(Step 1, 4 g, 14.6 mmol), acetonitrile (100 mL) and phenylmethanamine(1.72 g, 16.1 mmol) The resulting solution was stirred for 6 h at 65° C.in an oil bath and cooled to 25° C., the resulting mixture wasconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:1, v/v) toafford methyl 1-benzyl-4-methylazetidine-2-carboxylate as a light brownoil (2 g, 62%). LCMS: (ESI) m/z 220 [M+H].

Step 3. 1-Benzyl-4-methylazetidine-2-carboxylic acid

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with methyl1-benzyl-4-methylazetidine-2-carboxylate (Step 2, 2 g, 9.12 mmol), water(30 mL) and barium hydroxide (3.13 g, 18.3 mmol). The resulting solutionwas stirred for 2 h at 90° C. in an oil bath and cooled to 25° C., thepH was adjusted to 6 with hydrochloric acid (3 N). The product wasextracted with ethyl acetate (3×60 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated undervacuum to afford 1-benzyl-4-methylazetidine-2-carboxylic acid as acolorless oil (1.8 g, 96%). LCMS: (ESI) m/z 206 [M+H].

Example 74: Intermediate 2-176a. tert-Butyl4-methoxy-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

Step 1. tert-Butyl 4-methoxy-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

Trimethylsulfoxonium iodide (1.45 g, 6.55 mmol), dimethyl sulfoxide (20mL) and sodium hydride (157 mg, 6.54 mmol) were added to a 50-mLround-bottom flask fitted with a magnetic stir bar under an inertatmosphere. The resulting solution was stirred for 1 h at 0° C.tert-Butyl 3-methoxy-4-oxopiperidine-1-carboxylate (500 mg, 2.18 mmol)was added and the resulting solution was stirred at room temperature for5 h. The reaction mixture was quenched by the addition of water (20 mL)and extracted with ether (3×30 mL). The organic layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to give tert-butyl4-methoxy-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 94%). LCMS:(ESI) m/z 244 [M+H].

Example 75: Intermediate 2-198a.(4-Fluorophenyl)(2-methyl-1-oxa-6-azaspiro[2.5]octan-6-yl)methanone

Step 1. Piperidin-4-one trifluoroacetic acid salt

tert-Butyl 4-oxopiperidine-1-carboxylate (3 g, 15.0 mmol),dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added to a100-mL round-bottom flask with magnetic stir bar. The resulting solutionwas stirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum to give piperidin-4-one trifluoroacetic acidsalt which was used in next step without further purification.

Step 2. 1-(4-Fluorobenzoyl)piperidin-4-one

The title compound was prepared according to the procedure outline inExample 7 utilizing piperidin-4-one trifluoroacetic acid salt (Step 1,4.69 mmol) and 4-fluorobenzoic acid (1.44 g, 10.3 mmol) as startingmaterials followed by purification by column chromatography eluting withethyl acetate/petroleum ether (1:1 v/v). (800 mg, 77%). LCMS: (ESI) m/z222 [M+H].

Step 3. (4-Ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone

Tetrahydrofuran (10 mL) and potassium tert-butoxide (814 mg, 7.27 mmol)were added to a 100-mL 3-necked round-bottom flask equipped with amagnetic stir bar. A solution of ethyltriphenylphosphonium bromide (4.00g, 10.8 mmol) in tetrahydrofuran (10 mL) was added dropwise at roomtemperature over 10 min. To this mixture was added a solution of1-(4-fluorobenzoyl)piperidin-4-one (Step 2, 800 mg, 3.62 mmol) intetrahydrofuran (10 mL) dropwise with stirring at room temperature over2 min. The resulting solution was stirred for 3 h at 40° C. and thencooled to room temperature The resulting solution was diluted withn-hexane (50 mL), filtered, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:3 v/v) togive (4-ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone (250 mg,30%). LCMS: (ESI) m/z 234 [M+H].

Step 4.(4-Fluorophenyl)(2-methyl-1-oxa-6-azaspiro[2.5]octan-6-yl)methanone

(4-Ethylidenepiperidin-1-yl)(4-fluorophenyl)methanone (Step 3, 250 mg,1.07 mmol), 3-chloroperbenzoic acid (239 mg, 1.38 mmol) and chloroform(20 mL) were added to a 100-mL round-bottom flask with a magnetic stirbar. The resulting solution was stirred for 16 h at room temperature andthen washed with saturated aqueous sodium thiosulfate (30 mL) andsaturated aqueous sodium bicarbonate (10 mL). The mixture was extractedwith dichloromethane (5×20 mL). The organic layers were combined, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by column chromatography using ethyl acetate/petroleumether (1:4 v/v) to give(4-fluorophenyl)(2-methyl-1-oxa-6-azaspiro[2.5]octan-6-yl)methanone.LCMS: (ESI) m/z 250 [M+H].

Example 76: Intermediate 2-313a:N-[3-(3-chiorophenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide

A 100-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar and thermometer was charged with1-bromo-3-chlorobenzene (1 g, 5.22 mmol) and tetrahydrofuran (20 mL)followed n-BuLi (1.5 mL, 2.5 M in hexane) added dropwise at −78° C. Tothe reaction was added2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.11 g, 6.33 mmol)in tetrahydrofuran (5 mL) at −78° C. and stirred for 5 h at −78° C. in adry ice bath under nitrogen. The reaction was quenched with water (30mL). The product was extracted with dichloromethane (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (1:50to 1:10 v/v) to affordN-[3-(3-chlorophenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (800 mg,53%) as a white solid. LCMS: (ESI) m/z 288, 290 [M+H].

Example 77: Intermediate 2-235a4-(pyridin-2-yloxy)piperidine-1-carboxylate chloride

Step 1. Tert-butyl 4-(pyridin-2-yloxy)piperidine-1-carboxylate

A 100-mL 3-necked round-bottom flask equipped with a nitrogen balloonwas charged with pyridin-2-ol (500 mg, 5.26 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (3.17 g, 15.75 mmol),triphenylphosphine (4.14 g, 15.78 mmol), tetrahydrofuran (20 mL). Asolution of diethyl azodicarboxylate (2.75 g, 15.79 mmol) intetrahydrofuran (5 mL) was added at 0° C. After addition, the solutionwas stirred for 5 h at 23° C. The mixture was concentrated under vacuum.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (7:100 v/v) to afford tert-butyl4-(pyridin-2-yloxy)piperidine-1-carboxylate as a white solid (600 mg,41%). LCMS: (ESI) m/z 279 [M+H].

Step 2. 2-(piperidin-4-yloxy)pyridine dihydrochloride

A 100-mL round-bottom flask was charged with tert-butyl4-(pyridin-2-yloxy)piperidine-1-carboxylate (Step 1, 600 mg, 2.16 mmol)and dioxane (10 mL) followed by the addition of hydrochloric acid indioxane (3 M, 20 mL). The resulting solution was stirred for 3 h at 23°C. The resulting mixture was concentrated under vacuum to afford2-(piperidin-4-yloxy)pyridine dihydrochloride as a white solid which wasused without further purification (500 mg, >95%). LCMS: (ESI) mii 179[M+H].

Step 3. 4-(pyridin-2-yloxy)piperidine-1-carbonyl chloride

A 100-mL round-bottom flask was charged with triphosgene (107 mg, 0.36mmol) and dichloromethane (10 mL). 2-(piperidin-4-yloxy)pyridinedihydrochloride (Step 2, 150 mg, 0.60 mmol) andN,N-diisopropylethylamine (181.8 mg, 1.41 mmol) were added dropwise at0° C. The resulting solution was stirred for 3 h at 0° C. The mixturewas concentrated under vacuum to afford4-(pyridin-2-yloxy)piperidine-1-carbonyl chloride as a yellow solidwhich was used without further purification (150 mg, >95%). LCMS: (ESI)m/z 241, 243 [M+H].

The Intermediates in Table 34 were synthesized according to theprocedure above.

TABLE 34 LCMS: (ES) Intermediate No.: Precursor Used m/z [M + H]Intermediate 2-108X. 4- tert-butyl 4-hydroxypiperidine- 245, 247((5-methylisoxazol-3- 1-carboxylate and 5- yl)oxy)piperidine-1-methylisoxazol-3-ol carbonyl chloride Intermediate 2-109Y. 4- tert-butyl4-hydroxypiperidine- 244, 246 ((1-methyl-1H-pyrazol-4- 1-carboxylate and1-methyl-1H- yl)oxy)piperidine-1- pyrazol-4-ol carbonyl chloride

Example 78: Intermediate 2-339a.5-[(3-fluoro-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1. tert-butyl 4-fluoro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

A 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stirbar and thermometer was charged with a solution ofdimethylmethanesulfinyl iodide (13.8 g, 62.5 mmol) in dimethylsulphoxide (30 mL) followed by sodium hydride (1.5 g, 62.5 mmol, 60% wt)at 0-5° C. After 20 min of vigorous stirring tert-butyl3-fluoro-4-oxopiperidine-1-carboxylate (10.4 g, 47.9 mmol) in dimethylsulphoxide (10 mL) was added dropwise at 10° C. over 10 min. Theresulting solution was stirred for 16 h at 23° C. under nitrogen. Thereaction was quenched with water (30 mL). The product was extracted withethyl acetate (3×30 mL). The combined organic extracts were washed withbrine (20 mL), dried over anhydrous sodium sulfate and concentratedunder vacuum to afford tert-butyl4-fluoro-1-oxa-6-azspiro[2.5]octane-6-carboxylate (2.45 g, 17%) as ayellow oil which was used in next step without further purification.LCMS: (ESI) m/z 232 [M+H].

Step 2.tert-butyl-4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate

The title compound was prepared according to the [procedure outlined inExample 877 utilizing tert-butyl4-fluoro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (Step 1, 2.45 g, 7.08mmol) and 1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (1.5 g, 10.6mmol) followed purification by column chromatography eluting with ethylacetate/petroleum ether (1:2 v/v) (800 mg, 17%). LCMS: (ESI) m/z 444[M+H].

Step 3.5-[(3-fluoro-4-hydroxypiperidin-4-yl)methyl]-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

The title compound was prepared according to procedure outlined inExample 2a utilizing tert-butyl3-fluoro-4-hydroxy-4-([4-oxo-1-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate(Step 2, 760 mg, 1.72 mmol) (650 mg, >95%). LCMS: (ESI) m/z 344 [M+H].

Example 79: Intermediate 2-345a.1-(4-fluorophenyl)-5-(2-hydroxy-1-(4-hydroxypiperidin-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onehydrochloride

Step 1. tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate

A solution of tert-butyl4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (4.99 g, 18.5 mmol)in toluene (75 ml) was placed under nitrogen in a 500 mL round-bottomflask and cooled on a dry ice/acetone bath at −77° C. Diisobutylaluminumhydride (1.0 M in heptane, 40 ml, 40.0 mmol) was added dropwise bysyringe over 20 min. The solution was stirred for 2.5 hours beforeadding saturated aqueous NH₄Cl (12.5 mL) dropwise over 8 min. The samplewarmed to 23° C. and stirred for 16 h. The mixture was shaken with water(100 mL). The resulting emulsion was filtered on a Buchner funnel andthe filter cake was washed with EtOAc (50 mL). The layers wereseparated. The product was extracted with EtOAc (2×50 mL), then thecombined organic extracts were dried over sodium sulfate, filtered andevaporated under reduced pressure to provide an oil. The material wasdissolved in hexanes-EtOAc and purified by Biotage MPLC (100 g silicagel column, 10 to 60% EtOAc in hexanes) to provide tert-butyl4-(2-hydroxyethylidene)piperidine-1-carboxylate (3.71 g, 88%). ¹H NMR(300 MHz, CHLOROFORM-d) δ 5.50 (t, J=7.04 Hz, 1H), 4.15-4.23 (m, 2H),3.36-3.50 (m, 4H), 2.27 (dd, J=5.70 Hz, 2H), 2.19 (dd, J=5.70 Hz, 2H),1.48 (s, 9H). LCMS: (ESI) m/z 250 [M+Na].

Step 2. tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)ethylidene)piperidine-1-carboxylate

A solution of tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate(Step 1, 3.71 g, 16.3 mmol) in DMF (22 ml) was treated with imidazole(3.44 g, 50.5 mmol) and TBDMS-Cl (3.72 g, 24.7 mmol). The solution wasstirred at 23° C. for 72 h. The yellow solution was diluted with EtOAc(250 mL), washed with water (3×250 mL) and brine (2×250 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andevaporated to provide a colorless oil. The oil was dissolved in a few mLhexanes and purified by Biotage MPLC (100 g silica gel column, 0 to 6.5%EtOAc in hexanes) to provide tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)ethylidene)piperidine-1-carboxylate(5.37 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 5.40 (t, J=6.45 Hz, 1H), 4.21(d, J=6.45 Hz, 2H), 3.34-3.49 (m, 4H), 2.10-2.29 (m, 4H), 1.47 (s, 9H),0.91 (s, 9H), 0.08 (s, 6H). LCMS: (ESI) m/z 342 [M+H].

Step 3. tert-butyl2-((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

A stirred solution of tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)ethylidene) piperidine-1-carboxylate(Step 2, 5.37 g, 15.7 mmol) in chloroform (200 mL) was cooled on an icebath. To the reaction was added m-CPBA (<77%, 12.57 g, 56.1 mmol) beforeremoving the ice bath. The reaction was stirred for 2 days resulting information of a white precipitate. The reaction was quenched with aqueous10% sodium thiosulfate (250 mL) and aqueous saturated NaHCO₃ (250 mL).The mixture was shaken for 5 min and then partitioned. The product wasextracted further with dichloromethane (2×400 mL). The combined organiclayers were dried over magnesium sulfate and evaporated under reducedpressure to provide 5.74 g yellow liquid. The material was dissolved ina little hexanes/EtOAc and purified by Biotage MPLC (100 g silica gelcolumn, 0 to 10% EtOAc in hexanes) to provide tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate(2.55 g, 45%). ¹H NMR (300 MHz, CDCl₃) δ 3.60-3.86 (m, 4H), 3.36-3.53(m, 2H), 2.98 (t, J=5.57 Hz, 1H), 1.78 (ddd, J=13.49, 9.23, 4.25 Hz,2H), 1.38-1.66 (m, 11H), 0.91 (s, 9H), 0.07-0.12 (m, 6H). LCMS: (ESI)m/z 358 [M+H].

Step 4. tert-butyl4-(1-azido-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate

A solution of tert-butyl2-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate(Step 3, 179 mg, 0.501 mmol) in DMF (4 ml) was treated with ammoniumchloride (102 mg, 1.91 mmol) and sodium azide (153 mg, 2.35 mmol) andstirred at 90° C. for 5 h. The mixture was diluted with EtOAc (40 mL),washed with brine (2×40 mL) and water (3×40 mL). The combined organiclayers were dried over sodium sulfate, filtered, and evaporated underreduced pressure. The residue was dissolved in hexanes/EtOAc andpurified by Biotage MPLC eluting with EtOAc/Hexanes (10 g silica gelcolumn, 0 to 17% v/v) to provide tert-butyl4-(1-azido-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(77.2 mg, 39% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 4.79 (s, 1H), 4.01(dd, J=10.99, 3.08 Hz, 1H), 3.62-3.80 (m, 3H), 3.36 (dd, J=9.23, 3.08Hz, 1H), 2.92 (br s, 2H), 1.33-1.52 (m, 13H), 0.88 (s, 9H), 0.08 (s,6H). LCMS: (ESI) nm/z 401 [M+H].

Step 5. tert-butyl4-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate

In a 2-necked 50 mL round-bottom flask was added 10% Pd/C (49.0 mg,0.046 mmol Pd) under nitrogen. Methanol (3 mL) was added carefully bysyringe and then the apparatus was opened and a solution of tert-butyl4-(1-azido-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(Step 4, 1.15 g, 2.87 mmol) in MeOH (10 mL) was added by pipet followedby triethylamine (5 drops). The atmosphere was removed and replaced withhydrogen three times. The mixture was stirred under hydrogen (balloon, 1atm) for 24 h. The sample was filtered through Celite 545 on a Buchnerfunnel, and the filter cake was washed with MeOH (40 mL). The filtratewas evaporated under reduced pressure to provide tert-butyl4-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(1.07 g, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 4.25 (s, 1H), 3.63-3.80 (m,3H), 3.40 (dd, J=9.97, 7.62 Hz, 1H), 2.96 (br s, 3H), 1.04-1.57 (m,15H), 0.86 (s, 9H), 0.04 (s, 6H). LCMS: (ESI) m/z 375 [M+H].

Step 6. tert-butyl4-(1-(5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamido)-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate

A solution of tert-butyl4-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(Step 5, 922 mg, 2.46 mmol) in dichloromethane (30 ml) was treated with5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (571 mg, 2.58mmol), HATU (989 mg, 2.60 mmol), and triethylamine (1.72 mL, 12.3 mmol).The reaction was stirred at 23° C. for 4 days and diluted with EtOAc(250 mL). The organic layer was washed with saturated aqueous ammoniumchloride (250 mL), brine (250 mL), and water (2×250 mL). The combinedorganic layers were dried over sodium sulfate, filtered, treated withsilica gel, and evaporated under reduced pressure. The material waspurified by Biotage MPLC eluting with EtOAc/Hexanes (50 g silica gelcolumn, 0 to 50% v/v, isocratic elution at 42% EtOAc) to providetert-butyl4-(1-(5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamido)-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(841 mg, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.53-7.63 (m,2H), 7.25-7.41 (m, 3H), 6.35 (s, 2H), 4.62 (s, 1H), 3.91-4.08 (m, 2H),3.59-3.77 (m, 3H), 2.99 (br s, 2H), 1.22-1.59 (m, 13H), 0.82 (s, 9H),0.02 (d, J=4.40 Hz, 6H). LCMS: (ESI) m/z 578 [M+H].

Step 7. tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)-1-(1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)-4-hydroxypiperidine-1-carboxylate

A solution of tert-butyl4-(1-(5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamido)-2-((tert-butyldimethylsilyl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylate(Step 6, 180 mg, 0.311 mmol) and p-toluenesulfonic acid monohydrate (5.0mg, 0.026 mmol) in triethyl orthoformate (5.4 mL, 32.4 mmol) was stirredat 23° C. for 3.5 hours. The reaction was quenched with triethylamine(12 drops). The sample was dissolved in EtOAc/hexanes material at thesame stage from a previous run (20.1 mg, 0.035 mmol pyrazole startingmaterial) was added. The sample was purified by Biotage MPLC (10 gsilica gel column, 0 to 50% EtOAc in hexanes, with isocratic elution at16% EtOAc) to provide tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)-1-(1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)-4-hydroxypiperidine-1-carboxylate(130 mg, 64%) and used without further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 8.45 (s, 1H), 8.39 (s, 1H), 7.99-8.13 (m, 2H), 7.38-7.51 (m,2H), 5.22 (s, 1H), 5.06 (dd, J=10.11, 5.72 Hz, 1H), 4.14-4.25 (m, 1H),4.03-4.13 (m, 1H), 3.53-3.80 (m, 3H), 3.06 (br s, 3H), 1.61-1.74 (m,2H), 1.38 (s, 9H), 0.66 (s, 9H), −0.03 (d, J=9.67 Hz, 6H). LCMS: (ESI)m/z 588 [M+H].

Step 8.1-(4-fluorophenyl)-5-(2-hydroxy-1-(4-hydroxypiperidin-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onehydrochloride

The title compound was prepared according to the procedure outlined inExample 2a utilizing tert-butyl4-(2-((tert-butyldimethylsilyl)oxy)-1-(1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)ethyl)-4-hydroxypiperidine-1-carboxylate(Step 7, 124.5 mg, 0.212 mmol) as starting material (83.7 mg, 96%). ¹HNMR (300 MHz, DMSO-d₆) δ 8.85 (br s, 1H), 8.46-8.57 (m, 1H), 8.45 (s,1H), 8.39 (s, 1H), 8.01-8.13 (m, 2H), 7.37-7.49 (m, 2H), 5.44-5.99 (m,4H), 5.00 (dd, J=9.23, 5.42 Hz, 1H), 3.86-4.10 (m, 2H), 3.11-3.24 (m,1H), 2.80-3.11 (m, 3H), 1.94 (br s, 2H), 1.57-1.74 (m, 1H), 1.28 (br d,J=14.07 Hz, 1H). LCMS: (ESI) m/z 374 [M+H].

Example 80: Intermediate 2-515a.5-[(4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

Step 1. Tert-butyl4-hydroxy-4-([1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate

A 25-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with tert-butyl4-[[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate(Intermediate 28x, 1.000 g, 1.98 mmol), 4-methyl-1H-pyrazole (1.30 g,15.8 mmol), copper (I) iodide (0.754 g, 3.96 mmol), sodium carbonate(0.421 g, 3.97 mmol), (1S,2S)-cyclohexane-1,2-diamine (0.046 g, 0.40mmol) and dioxane (7 mL). The resulting solution was stirred for 12 h at120° C. under nitrogen. After cooling to 23° C., the mixture was dilutedwith water (10 mL). The product was extracted with dichloromethane (3×20mL) and the organic layers were combined, washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography eluting withacetate/petroleum ether (35:65, v/v) to afford tert-butyl4-hydroxy-4-([1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate(0.140 g, 14%). LCMS: (ESI) m/z 506 [M+H].

Step 2.5-[(4-hydroxypiperidin-4-yl)methyl]-1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

The title compound was prepared according to the procedure outlined inExample 2, utilizing tert-butyl4-hydroxy-4-([1-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl)piperidine-1-carboxylate,Step 1, as starting material (0.112 g, 95%). LCMS: (ESI) m/z 406 [M+H].

The Intermediates in Table 35 were prepared according to the procedureoutlined above.

TABLE 35 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-517aa. 1- tert-butyl 4-[[1-(4- 392(4-(1H-pyrazol-1-yl)phenyl)- bromophenyl)-4-oxo-5-((4-hydroxypiperidin-4- 1H,4H,5H-pyrazolo[3,4-yl)methyl)-1,5-dihydro-4H- d]pyrimidin-5- pyrazolo[3,4-d]pyrimidin-yl]methyl]- 4-one, TFA salt 4-hydroxypiperidine-1- carboxylate and1H-pyrazole

Example 81: Intermediate 2-619a.4-(4-Oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoic acid

The title compound was prepared according to procedures outlined inExample 21, Step 1, Step 2, utilizing 4-hydrazinylbenzoic acidhydrochloride (4.95 g, 26.2 mmol) as starting material LCMS: (ES) m/z257 [M+H].

The Intermediates in Table 36 were prepared according to the procedureoutlined above:

TABLE 36 MS (ESI, m/z) Intermediate No.: Precursor Used [M + H].Intermediate 2-537aa 1-(4- (4-methylphenyl)hydrazine 227Methylphenyl)-1H,4H,5H-pyrazolo[3,4- hydrochloride d]pyrimidin-4-oneIntermediate 2-366a. 1-(4-(1H-1,2,3- 1-(4-hydrazinylphenyl)-1H- 280triazol-1-yl)phenyl)-1H-pyrazolo[3,4- 1,2,3-triazole hydrochlorided]pyrimidin-4 (5H)-one and 1-(4-(2H- and 2-(4-hydrazinylphenyl)-1,2,3-triazol-1-yl)phenyl)-1H-pyrazolo[3,4- 1H-1,2,3-triazoled]pyrimidin-4 (5H)-one hydrochloride prepared from4-(2H-1,2,3-triazol-2- yl)aniline and 4-(1H-1,2,3- triazol-2-yl)anilineIntermediate 2-3111. 1-(4-bromo-3- (4-bromo-3- 305, 307methylphenyl)-1H-pyrazolo[3,4- methylphenyl)hydrazine d]pyrimidin-4(5H)-one prepared according to procedure used for intermediate 2-28 from4- bromo-3-methylaniline Intermediate 2-3112. 1-(4-fluoro-3-(4-fluoro-3- 245 methylphenyl)-1H-pyrazolo[3,4- methylphenyl)hydrazined]pyrimidin-4 (5H)-one starting from 4-fluoro-3- methylbenzenamine as itis outlined in procedure used for intermediate 2-28

Example 82: Intermediate 332aa.7-(4-fluorophenyl)-6-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4 (7H)-one

Step 1. 2-(2-oxo-2-phenylethyl(malononitrile

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar wascharged with propanedinitrile (1.39 g, 21.04 mmol), ethanol (100 mL) and2-bromo-1-phenylethan-1-one (5 g, 25.1 mmol) followed by sodiumhydroxide (1.26 g, 31.5 mmol) in ethanol (25 mL) added dropwise withstirring over 3 min. Stirring continued for 1 h at 23° C. beforeconcentrating the reaction under vacuum. The residue was diluted withwater (50 mL). The product was extracted with ethyl acetate (5×50 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether (1:1 v/v) toafford 2-(2-oxo-2-phenylethyl) malononitrile (1.2 g, 31%). LCMS: (ESI)m/z 185[M+H].

Step 2. 2-amino-1-(4-fluorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile

A 10-mL MW tube was charged with 2-(2-oxo-2-phenylethyl)malononitrile(Step 1, 340 mg, 1.85 mmol), 4-fluoroaniline (204 mg, 1.84 mmol),ethanol (3 mL), hydrochloric acid (0.1 mL, 12N). The reaction mixturewas irradiated with a microwave for 1 h at 120° C. and cooled to 23° C.The pH was adjusted to 8 with saturated sodium carbonate and the productwas extracted with ethyl acetate (5×30 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography elutingwith ethyl acetate/petroleum ether (1:1 v/v) to afford2-amino-1-(4-fluorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (180 mg,35%). LCMS: (ESI) m/z 278 [M+H].

Step 3. 7-(4-fluorophenyl)-6-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,thermometer and condenser was charged with2-amino-1-(4-fluorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (Step 2,90 mg, 0.32 mmol), formic acid (10 mL) and water (0.5 mL). The resultingsolution was stirred for 1.5 h at 100° C. and cooled to 23° C. Thesolvent was removed under vacuum and the residue was diluted with water(20 mL). The product was extracted with ethyl acetate (5×20 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated to afford7-(4-fluorophenyl)-6-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4 (7H)-one (120mg) and used without further purification. LCMS: (ESI) m/z 306[M+H].

Example 83: Intermediate 2-537a.1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1.1-[4-(Dibromomethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with1-(4-methylphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (900 mg, 3.98mmol), tetrachloromethane (60 mL, 619 mmol), N-bromosuccinimide (2.25 g,12.6 mmol), benzoyl peroxide (2.03 g, 7.90 mmol). The solution wasstirred for 14 h at 80° C. in an oil bath After cooling to 25° C., thereaction was quenched with water (50 mL). The product was extracted withdichloromethane (4×40 mL). The combined organic layers were washed withbrine (30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography eluting with dichloromethane/methanol (20:1, v/v) to give1-[4-(dibromomethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one as ayellow solid (1 g, 65%). LCMS: (ES) m/z 383, 385, 387 [M+H].

Step 2. 4-[4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde

A 100-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with1-[4-(dibromomethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(Step 1, 1 g, 2.60 mmol), dioxane (20 mL), water (40 mL) and calciumcarbonate (260 mg, 2.55 mmol). The resulting solution was stirred for 1h at 100° C. in an oil bath. After cooling to 25° C., the reaction waswith water (20 mL). The solids were collected by filtration, washed withwater (2×20 mL) and dried in an oven to give4-[4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde as a yellowsolid (900 mg, >95%). LCMS: (ES) m/z 241 [M+H].

Step 3.1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith 4-[4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (Step2, 500 mg, 2.08 mmol) and tetrahydrofuran (20 mL). This was followed bythe addition of sodium borohydride (463 mg, 12.2 mmol) in portions at 0°C. The solution was stirred for 4 h at 25° C. The reaction was quenchedwith water (10 mL) and the product was extracted with ethyl acetate(3×20 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with dichloromethane/methanol(50:1-20:1, v/v) to afford1-[4-(hydroxymethyl)phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one asan off-white solid (100 mg, 20%). LCMS: (ES) m/z 243 [M+H].

Example 84: Intermediate 2-665a.1-(4-cyclobutylphenyl)-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneTFA salt

Step 1. Tert-butyl4-[[1-(4-cyclobutylphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate

A 100-mL round-bottom flask fitted with a nitrogen balloon and magneticstir bar was charged with tert-butyl4-[[1-(4-bromophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate(500 mg, 0.99 mmol), tetrahydrofuran (30 mL), palladium acetate (11.1mg, 0.05 mmol), S-Phos (30.5 mg, 0.07 mmol), bromo(cyclobutyl)zinc (1.98mL, 4.94 mmol). The reaction was stirred for 16 h at 25° C. undernitrogen and then quenched with water (50 mL). The product was extractedwith ethyl acetate (3×40 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:1, v/v) to afford tert-butyl4-[[1-(4-cyclobutylphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate(50 mg, 11%). LCMS: (ES) m/z 480 [M+H].

Step 21-(4-cyclobutylphenyl)-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,TFA salt

The title compound was prepared according to the method outlined inExample 2 utilizing tert-butyl4-[[1-(4-cyclobutylphenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxypiperidine-1-carboxylate (Step 1, 50 mg, 0.10 mmol) asstarting material (52 mg). LCMS: (ES) m/z 380 [M+H].

Example 85: Intermediate 2-869a.4-[1-[2-(Benzyloxy)ethyl]-1H-pyrazol-4-yl]benzoic acid

Step 1. Ethyl 4-(1H-pyrazol-4-yl)benzoate

A 500-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with ethyl4-bromobenzoate (2 g, 8.73 mmol),4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.3 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (700 mg, 0.86 mmol), potassium carbonate (26.3 mg,0.19 nmol), 1,4-dioxane (200 mL) and water (20 mL). The resultingsolution was stirred for 10 h at 100° C. in an oil bath under nitrogen.After cooling to 25° C., the reaction was quenched with water (200 mL).The product was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography elutingwith ethyl acetate/petroleum (4:1, v/v) to afford ethyl4-(1H-pyrazol-4-yl)benzoate as a yellow solid (360 mg, 19%). LCMS: (ESI)m/z 217 [M+H].

Step 2. Ethyl 4-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]benzoate

The title compound as prepared according to the procedure outlined inExample 865, Step 1, utilizing ethyl 4-(1H-pyrazol-4-yl)benzoate (Step1, 80 mg, 0.37 mmol), and [(2-bromoethoxy)methyl]benzene (240 mg, 1.12mmol) as starting materials which was used in the next step withoutfurther purification (100 mg). LCMS: (ESI) m/z 351 [M+H]

Step 3. 4-[1-[2-(Benzyloxy)ethyl]-1H-pyrazol-4-yl]benzoic acid

The title compound as prepared according to the procedure outlined inExample 10, Step 2, utilizing ethyl4-[1-[2-(benzyloxy)ethyl]-1H-pyrazol-4-yl]benzoate (Step 2, 100 mg, 0.29mmol) as starting material LCMS: (ESI) m/v 323 [M+H].

Example 85a: Intermediate 2-131.trans-4-(difluoromethoxy)cyclohexane-1-carboxylic acid

Step 1. Methyl (1r,4r)-4-(difluoromethoxy)cyclohexane-1-carboxylate

A 50-mL 3-necked round-bottom fitted with a nitrogen balloon, magneticstir bar condenser and thermometer was charged with methyltrans-4-hydroxycyclohexane-1-carboxylate (200 mg, 1.26 mmol),acetonitrile (20 mL) and cuprous iodide (239 mg, 1.25 mmol). To thereaction was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (715 mg,4.01 mmol) dropwise with stirring at 65° C. over 15 min. The solutionwas stirred for 1 h and cooled to 25° C. The reaction was quenched withwater (15 mL). The product was extracted with ethyl acetate (3×30 mL).The organic layers were combined, washed with brine (3×20 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (1:10-1:5, v/v) to afford the title compound(200 mg). GCMS: m/z 208.

Step 2. Trans-4-(Difluoromethoxy)cyclohexane-1-carboxylic acid

The title compound was prepared according to the procedure described inExample 10, Step 2, utilizing methyl(1r,4r)-4-(difluoromethoxy)cyclohexane-1-carboxylate (100 mg, 0.48mmol), (Intermediate 2-131, 40 mg, 43%). LCMS: (ESI) m/z 193 [M−1].*Column: XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm. Mobile phaseA: aqueous trifluoroacetic acid (0.1%)/Mobile phase B: acetonitrile.Gradient: 25% B to 45% B over 7 min. Detector: 220 and 254 nm.

Methods for the Synthesis of Compounds of Formula (I) Method A Example86:5-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-1)

To a solution of5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid (Intermediate 2-2, 21 mg, 0.08 mmol) in1,2-dichloroethane (0.2 mL) was added 3-phenylbutanoic acid (0.2 M in1,2-dichloroethane, 0.480 mL, 0.096 mmol), DIPEA (0.070 mL, 0.4 mmol)and HATU (37 mg, 0.096 mmol). The reaction mixture was stirred at 50° C.for 16 h. The reaction mixture was cooled to room temperature, dilutedwith dichloromethane and washed with water. The crude product waspurified by preparative HPLC (Method 6) to afford5-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-1, 13 mg, 38%). LCMS (ESI) m/z 410.23 [M+H]

Method D Example 87:N-([1,1′-biphenyl]-4-yl)-4-hydroxy-N-methyl-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxamide(I-4)

The [1,1′-biphenyl]-4-yl(methyl)carbamic chloride solution (prepared bythe addition of triphosgene (3 mg, 11 μmol) to a solution ofN-methyl-[1,1′-biphenyl]-4-amine (5.5 mg, 30 μmol) and DIPEA (11 μL, 60μmol) in 1,2-dichloroethane (200 μL) and the resulting solution wasstirred at room temperature for 2.5 h and used without furtherpurification) was added to a suspension of5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,hydrochloric acid salt (Intermediate 2-2a, 9 mg, 30 μmol) and DIPEA (11μL, 60 μmol) in 1,4-dioxane (200 μL). The resulting solution was stirredfor 16 h at room temperature, concentrated under reduced pressure andthen partitioned between saturated aqueous sodium bicarbonate and ethylacetate. The ethyl acetate was separated and combined with a secondethyl acetate extract. The combined extracts were concentrated underreduced pressure and the crude product was purified by preparative HPLC(Method 6) to affordN-([1,1′-biphenyl]-4-yl)-4-hydroxy-N-methyl-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxamide(I-4, 6.5 mg, 46%). LCMS: (ESI) m/z 473.06 [M+H].

Method E Example 88:1-(3-((Cyclohexyl(ethyl)amino)methyl)phenyl)-5-((1-(cyclopropane-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-5)

N-Ethylcyclohexanamine (0.2 M 1,4-dioxane, 180 μL, 36 μmol) was added toa suspension of potassium (bromomethyl)trifluoroborate (7 mg, 36 μmol)in 1,4-dioxane (162 μL) and water (18 μL). The resulting mixture wassealed and heated at 80° C. for 6 h. The reaction mixture was cooled toroom temperature.1-(3-bromophenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-31, 0.2 M solution in DMF, 15.0 μL, 30 μmol) and cesiumcarbonate (1.0M in methanol, 90 μL, 90 μmol) were added and nitrogen gaswas bubbled through the resulting mixture.Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium (II) methyl-tert-butyl ether adduct (0.01 M in 1,4-dioxane, 75μL, 0.75 μmol) was added and the reaction mixture was heated at 100° C.for 16 h. The reaction mixture was diluted with brine (500 μL) andextracted with ethyl acetate (2×500 μL). The organic layers werecombined, concentrated, and purified by preparative HPLC (Method 8) toafford1-(3-((cyclohexyl(ethyl)amino)methyl)phenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-5, 3.1 mg, 19%). LCMS: (ESI) m/z 533.56 [M+H].

Method H Example 89:5-((1-(Cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-8)

1-(4-Bromophenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-30, 0.05 M in 1:1 toluene:DMF, 600 μL, 30 μmol),(3-(trifluoromethyl)phenyl)boronic acid (0.2 M in 1,4-dioxane, 270 μL,54 μmol), potassium carbonate (1.0 M aqueous, 90 μL, 90 μmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexwith dichloromethane (0.02 M in 1,2-dichloroethane, 150 μL, 3 μmol) werecombined and heated at 80° C. under nitrogen for 14 h. The reactionmixture was cooled to room temperature. Ethyl acetate (500 μL) andsodium hydroxide (1.0 M aqueous, 400 μL) were added. The organic phasewas separated and the aqueous layer was extracted with ethyl acetate(500 μL). The combined organic phases were concentrated and purified bypreparative HPLC (Method 6) to give 5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-8, 3.2 mg, 20%). LCMS: (ESI) nm/z 538.37 [M+H].

Method I Example 90:5-((4-Hydroxy-1-(4-((pyrimidin-2-yloxy)methyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-9)

In a 20 mL vial was added5-((4-hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-7, 0.030 g, 0.075 mmol) and sodium hydride (60% inmineral oil, 6 mg, 0.151 mmol) in portions at 0° C. in DMF (0.503 mL).The reaction was stirred for 5 min and then 2-chloropyrimidine (0.09 g,0.075 mmol) was added to give a brown suspension. The reaction wasstirred at 23° C. for 16 h. The DMF was removed under reduced pressureand the crude material was purified by column chromatography (Biotage,25 g column, eluting with 0-10% methanol/dichloromethane gradient) toprovide5-((4-hydroxy-1-(4-((pyrimidin-2-yloxy)methyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-9, 8.2 mg, 23%). LCMS: (ESI) m/z 476.19 [M+H].

Method J Example 91:4-((4-(4-Hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carbonyl)benzyl)oxy)benzonitrile(I-10)

In a 20 mL vial was added5-((4-hydroxy-1-(4-(hydroxymethyl)benzoyl)piperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-7, 30 mg, 0.075 mmol), 4-hydroxybenzonitrile (9.89 mg,0.083 mmol) and a solution of triphenylphosphine (0.022 g, 0.083 mmol)in tetrahydrofuran (0.503 mL). Diisopropyl azodicarboxylate (0.016 mL,0.083 mmol) was added and the reaction was stirred for 3 h at 23° C. Thesolution was diluted with ethyl acetate (30 mL) and washed withsaturated aqueous ammonium chloride (20 mL) and saturated aqueous sodiumbicarbonate (20 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated. The crude product was purified by preparativeHPLC (Method 1) to provide4-((4-(4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carbonyl)benzyl)oxy)benzonitrile (I-10, 3.4 mg, 9%). LCMS: (ESI) m/z 499.23 [M+H].

Method K Example 92:2-(3-(5-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)aceticacid (I-11)

2-(3-(4-Oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)aceticacid (prepared with a similar procedure outline in procedure used forintermediate 2-28 utilizing Methyl 2-(3-aminophenyl) acetate as startingmaterial followed by procedure outlined in Example 21 utilizing Methyl2-(3-hydrazinylphenyl)acetate as starting material which led to in situhydrolysis of the methyl ester) (180 mg, 0.67 mmol), cesium carbonate(652 mg, 2.00 mmol), DMF (10 mL) and6-benzoyl-1-oxa-6-azaspiro[2.5]octane (Intermediate 2-36, 174 mg, 0.80mmol) were added to a 100-mL round-bottom flask fitted with magneticstir bar, condenser and thermometer. The resulting solution was stirredfor 3 h at 100° C. The reaction was then quenched by the addition ofwater (20 mL). The resulting solution was extracted with dichloromethane(5×20 mL) and the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by preparative HPLC* to give2-(3-(5-((I-benzoyl-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)acetic acid (I-11, 34 mg, 10%). ¹H NMR (300 MHz, CD₃OD) δ 8.29-8.28 (m,1H), 8.28-8.20 (m, 1H), 8.01 (s, 1H), 7.85-7.83 (m, 1H), 7.47-7.34 (m,7H), 4.36-4.34 (m, 1H), 4.14 (s, 2H), 3.57-3.30 (m, 5H), 1.81-1.67 (m,3H), 1.45-1.42 (m, 1H). LCMS: (ESI) m/z 488.39 [M+H]. *Column: WatersXBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm.Mobile phase A: 0.05% aqueous ammonium bicarbonate/Mobile phase B:acetonitrile. Gradient: 3% B to 10% B over 8 min. Detector: 220 and 254nm.

Method L Example 93:5-((1-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-12)

5-((1-(4-Bromobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-3, 0.2 M solution in DMF, 150 μL, 30 μmol),1,2,3,4-tetrahydroisoquinoline (0.2 M solution in 1,4-dioxane, 300 μL,60 μmol) and cesium carbonate (39 mg, 120 μmol) were combined in a 2 mLreaction vial which was then purged with nitrogen. In a separate vessel,BINAP (0.05 M 1,4-dioxane, 4 mL) was combined with palladium (II)acetate (0.1 M 1,4-dioxane, 1.33 mL). The mixture was stirred at roomtemperature under nitrogen for 5 minutes. The preformed catalystsuspension (120 μL) was added to the reaction vial. The vial was sealedand heated at 100° C. for 16 h. The reaction mixture was partitionedbetween ethyl acetate (500 μL) and brine (500 μL). The organic layer wasremoved and concentrated. The crude product was purified by preparativeHPLC (Method 3) to afford5-((1-(4-(3,4-dihydroisoquinolin-2(1H)-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-12, 2 mg, 15%). LCMS: (ESI) m/z 499.17 [M+H].

Method R Example 94:5-((1-(2-Aminobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-17)

5-((4-Hydroxy-1-(2-nitrobenzoyl)piperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,utilizing5-((4-Hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-18) and 2-nitrobenzoic acid asstarting materials), (100 mg, 0.21 mmol), palladium on carbon (10% wt,18 mg) and methanol (20 mL) were added to a 50-mL round-bottom flaskfitted with a hydrogen balloon and a magnetic stir bar. The resultingsolution was stirred for 16 h at room temperature and filtered to removesolids. The filtrate was concentrated under vacuum and the crude productwas purified by preparative HPLC* to give5-((1-(2-aminobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-17, 11 mg, 11%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.34 (s,1H), 8.05 (d, 2H), 7.58 (t, 2H), 7.42 (t, 1H), 7.10-7.04 (m, 1H),6.99-6.96 (m, 1H), 6.69 (d, 1H), 6.55 (t, 1H), 5.12 (br s, 2H), 4.96 (s,1H), 4.05 (s, 2H), 3.32-3.15 (m, 4H), 1.66-1.40 (m, 4H) ppm. LCMS: (ESI)m/z 445.10 [M+H]. *Column: Waters XBridge BEH Shield RP18 OBD PrepColumn, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.5% aqueous ammoniumbicarbonate/Mobile phase B: acetonitrile. Gradient: 30% B to 70% B over10 min. Flow rate: 20 mL/min. Detector: 254 nm.

Method S Example 95:5-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(2-hydroxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-18)

5-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand dichloromethane (10 mL) were added to a 50-mL 3-necked round-bottomflask fitted with a magnetic stir bar and thermometer. This was followedby the addition of boron tribromide (0.22 mL, 2.00 equiv) at 5° C. Theresulting solution was stirred for 30 min at room temperature. Thereaction was then quenched by the addition of methanol and concentratedunder vacuum. The residue was purified by column chromatography elutingwith dichloromethane/methanol (30:1 v/v). The product was furtherpurified by preparative HPLC* to give5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-1-(2-hydroxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-18, 9 mg, 9%). LCMS: (ESI) m/z 446.12.*Column: Waters XSelect CSH C18OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05%aqueous ammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 5%B to 49% B over 7 min. Detector: 220 and 254 nm.

Method W Example 96:3-(5-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzoicacid (I-22)

Methyl3-(5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzoate (prepared according to procedure outlinein Method A utilizing Methyl3-(5-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzoatetrifluoroacetic acid salt (Intermediate 2-20) and benzoic acid (60 mg,0.12 mmol), lithium hydroxide (6 mg, 0.26 mmol), water (5 mL) andtetrahydrofuran (10 mL) were added to a 100-mL round-bottom flask fittedwith magnetic stir bar. The resulting solution was stirred for 16 h atroom temperature. The pH value of the solution was adjusted to 2 withhydrochloric acid (6.0 M aqueous) and then extracted with ethyl acetate(3×30 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by preparative HPLC* to give3-(5-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzoicacid (I-22, 26 mg, 17%). ¹H NMR (300 MHz, CD₃OD) δ 8.62 (s, 1H), 8.27(s, 1H), 8.19 (s, 1H), 8.06 (d, 1H), 7.94 (d, 1H), 7.51-7.35 (m, 6H),4.88 (s, 1H), 4.34-4.30 (m, 1H), 4.12-4.06 (m, 1H), 3.61-3.57 (m, 1H),3.49-3.37 (m, 2H), 1.91-1.52 (m, 3H), 1.50-1.32 (m, 1H) ppm. LCMS: (ESI)m/z 474.22 [M+H]. *Column: Waters XBridge BEH Shield RP18 OBD PrepColumn, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 10 mM aqueousammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 10% B to75% B over 10 min. Flow rate: 25 mL/min. Detector: 220 and 254 nm.

Method X Example 97:5-((1-(4-(Cyclopropylamino)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-23)

(4-(4-Hydroxy-4-((4-oxo-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carbonyl)phenyl)boronicacid (Prepared according to the procedure described in Method utilizing5-((4-Hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-18) and4-(dihydroxyboranyl)benzoic acid as starting materials) (250 mg, 0.53mmol), cyclopropylamine (60 mg, 1.05 mmol), copper (II) acetate (240 mg,0.53 mmol), pyridine (125 mg, 1.58 mmol), dichloromethane (30 mL) and 4Å molecular sieves (200 mg) were added to a 100 mL round-bottom flaskfitted with a magnetic stir bar. The resulting solution was stirred for16 h at room temperature. The solids were filtered and the filtrate wasconcentrated under vacuum. The residue was first purified by silica gelcolumn chromatography eluting with dichloromethane/methanol (20:1 v/v)and then further purified by preparative HPLC* to give5-((1-(4-(cyclopropylamino)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-23, 11 mg, 4%). ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 8.07-7.93 (m,3H), 7.64-7.26 (m, 5H), 6.75-6.73 (m, 2H), 4.23-3.98 (m, 3H), 3.48-3.08(m, 3H), 2.55-2.31 (m, 1H), 2.08-1.40 (m, 4H), 0.90-0.65 (m, 2H),0.65-0.40 (m, 2H) ppm. LCMS: (ESI) m/z 485.22 [M+H]. *Column: WatersXBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm.Mobile phase A: 0.1% aqueous ammonium hydroxide/Mobile phase B:acetonitrile. Gradient: 25% B to 46% B over 8 min. Detector: 220 and 254nm.

Method B Example 98

1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-28, 130 mg, 0.28 mmol),dichloromethane (150 mL) and triethylamine (152 mg, 1.50 mmol) wereadded to a 250-mL round-bottom flask fitted with a magnetic stir bar.The relevant carbamoyl or acid chloride (0.87 mmol) was added dropwiseat 0° C. The resulting solution was stirred for 16 h at room temperatureand then quenched by addition of water (20 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The crude product was purified by preparative HPLC with thefollowing conditions: Column: Waters SunFire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×150 mm. Mobile phase A: 0.05% aqueous ammoniumbicarbonate/Mobile phase B: acetonitrile. Detector: 220 and 254 nm.

Method C Example 99:N-(4′-(4-Hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)ethenesulfonamide(I-45)

5-((1-(2′-Amino-[1,1′-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(Intermediate 2-38, 40 mg, 0.090 mmol), dichloromethane (10 mL) andtriethylamine (30.7 mg, 0.30 mmol) were added to a 100-mL round-bottomflask fitted with a magnetic stir bar and thermometer. A solution of2-chloroethane-1-sulfonyl chloride (17 mg, 0.10 mmol) in dichloromethane(5 mL) was added dropwise at 0° C. The resulting solution was stirredfor 30 min at 0° C. The reaction was then quenched by the addition ofwater (10 mL). The resulting solution was extracted with dichloromethane(4×20 mL) and the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by preparative HPLC* to affordN-(4′-(4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)ethenesulfonamide(I-45. 11 mg, 23%). ¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 8.07 (s,1H), 7.56-7.46 (m, 5H), 7.40-7.31 (m, 3H), 6.57-6.51 (m, 1H), 6.04 (d,1H), 5.87 (d, 1H), 4.42-4.38 (m, 1H), 4.22-4.12 (m, 2H), 4.00 (s, 3H),3.72-3.69 (m, 1H), 3.52-3.46 (m, 2H), 3.46-3.32 (m, 1H), 1.87-1.65 (m,3H), 1.50-1.47 (m, 1H) ppm. LCMS: (ESI) m/z 549.11 [M+H]. *Column:Waters XBridge BEH Shield RP18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150mm. Mobile phase A: 10 mM aqueous ammonium bicarbonate/Mobile phase B:acetonitrile. Gradient: 16% B to 42% B over 7 min. Detector: 220 and 254nm.

Method F Example 100:(R)—N-(1-(4-Hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidin-1-yl)-1-oxo-3-phenylpropan-2-yl)ethenesulfonamide(I-46)

5-((1-(D-phenylalanyl)-4-hydroxypiperidin-4-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-onetrifluoroacetic acid (prepared according to the procedure outlined inExample 20, using TFA than HCl in Step 2, utilizing2S)-2-benzyl-3-[[(tert-butoxy)carbonyl]amino]propanoic acid and5-((4-hydroxypiperidin-4-yl)methyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-onetrifluoroacetic acid salt (Intermediate 2-2) as starting materials (200mg, 0.49 mmol), dichloromethane (20 mL) and triethylamine (197 mg, 1.95mmol) were added to a 100-mL round-bottom flask fitted with a magneticstir bar and thermometer. A solution of 2-chloroethane-1-sulfonylchloride (86 mg, 0.53 mmol) in dichloromethane (5 mL) was added at 0° C.The resulting solution was stirred for 2 h at 0° C. The reaction wasthen quenched by the addition of water (10 mL). The resulting solutionwas extracted with dichloromethane (3×20 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by preparative HPLC* to afford(R)—N-(1-(4-hydroxy-4-((1-methyl-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidin-1-yl)-1-oxo-3-phenylpropan-2-yl)ethenesulfonamide (I-46, 28 mg, 11%). LCMS: (ESI) m/z 501.09 [M+H].*Column: Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×150 mm.Mobile phase A: 0.05% aqueous ammonium bicarbonate/Mobile phase B:acetonitrile. Gradient: 15% B to 60% B over 8 min then 100% B for 4 min.Detector: 220 and 254 nm.

Example 101:4-(3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methylpiperidine-1-carboxamide(I-49)

3-((1-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(piperidin-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-onetrifluoroacetic acid salt (Intermediate 2-47, 100 mg, 0.18 mmol),triethylamine (36 mg, 0.36 mmol) and dichloromethane (20 mL) were addedto a 50-mL round-bottom flask fitted with a nitrogen inlet and magneticstir bar. A solution of methylcarbamic chloride (20 mg, 0.21 mmol) indichloromethane (5 mL) was then added dropwise with stirring at roomtemperature. The resulting solution was stirred for 1 h at roomtemperature. The reaction was then quenched by the addition of water (10mL) and extracted with ethyl acetate (4×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC* toafford4-(3-((I-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methylpiperidine-1-carboxamide(I-49, 35 mg, 39%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.48-7.44(m, 2H), 7.29-7.24 (m, 3H), 6.51-6.48 (m, 2H), 6.05 (br s, 1H),5.03-4.91 (m, 1H), 4.65-4.62 (m, 1H), 4.13-4.10 (m, 3H), 4.02 (s, 2H),3.54-3.36 (m, 2H), 2.91-2.80 (m, 2H), 2.59 (d, 3H), 1.94-1.29 (m, 8H).LCMS: (ESI) m/z 511.36 [M+H]. *Column: Waters XBridge BEH Shield RP18OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 0.05%aqueous ammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 20%B to 52% B over 18 min. Detector: 220 and 254 nm.

Method G Example 102:7-(3-(Aminomethyl)phenyl)-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one(I-51)

3-(3-((1-(4-(4-Fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile(120 mg, 0.25 mmol), palladium on carbon (10% wt, 10 mg), Raney nickel(10 mg), lithium hydroxide (10 mg, 0.42 mmol) and methanol (10 mL) wereadded to a 25-mL pressure tank reactor (5 atm) fitted with a magneticstir bar. The mixture was placed under a hydrogen atmosphere and stirredfor 30 min at room temperature. The solids were removed by filtrationand the filtrate was concentrated under reduced pressure. The residuewas purified by preparative HPLC* to give7-(3-(aminomethyl)phenyl)-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one(I-51, 26 mg, 21%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.65 (s,1H), 7.57-7.50 (m, 1H), 7.48-7.44 (m, 4H), 7.37-7.35 (m, 1H), 7.30-7.24(m, 2H), 6.69 (d, 1H), 4.97 (s, 1H), 4.23-4.12 (m, 1H), 4.05 (s, 2H),3.79 (s, 2H), 3.52-3.37 (m, 2H), 3.32-3.01 (m, 2H), 1.74-1.23 (m, 4H)ppm. LCMS: (ESI) m/z 476.30 [M+H]. *Column: Waters XBridge BEH ShieldRP18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm. Mobile phase A: 10 mMaqueous ammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 7%B to 35% B over 10 min. Flow rate: 25 mL/min. Detector: 220 and 254 nm.

Method O Example 103:4-({1-[4-(Benzyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide(I-474)

4-Hydroxy-4-((1-(4-hydroxyphenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-N,N-dimethylpiperidine-1-carboxamide(0.1 M in DMF, 300 μL, 30 μmol) was combined with benzyl bromide (0.2 MDMF, 225 μL, 45 μmol, 1.5 equivalents) over solid potassium carbonate(21 mg, 150 μmol, 5 equivalents). The mixture was agitated at 50° C. for18 h. The volatiles were removed under a stream of nitrogen, and thesolids were partitioned between ethyl acetate (1.0 mL) and water (0.5mL). The organic layer was removed, concentrated, and purified by masstriggered preparative HPLC (Method 4) to afford4-({1-[4-(benzyloxy)phenyl]-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl}methyl)-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide(5.5 mg, 37%). LCMS: (ESI) m/z 503.34 [M+H]

Method P Example 104: 3-(Pyrrolidin-1-yl)propyl4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate(I-486)

A 2 mL reaction vial was charged with4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carbonylchloride (0.2M DMF, 150 μL, 30 μmol), N,N-diisopropylethylamine (26 μL,150 μmol), and 2-(pyrrolidin-1-yl)ethanol (0.2M DMF, 225 μL, 45 μmol).The mixture was agitated at room temperature for 12-18 h. The resultingsolution was concentrated, and the crude residue was diluted with brine(500 μL) and extracted with 3:1 ethyl acetate/methanol (2×500 μL). Theorganic layers were deposited onto a tosic acid cation exchangecartridge (500 mg) for solid phase extraction. The solid phase waswashed with 3 mL of 3:1 ethyl acetate/methanol (3 mL), and product wasreleased with 2M ammonia in methanol (3 mL). The methanolic eluent wascollected, concentrated, and purified by mass triggered preparative HPLC(Method 6) to yield 3-(pyrrolidin-1-yl)propyl4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate(3.9 mg, 26%). LCMS: (ESI) m/z 499.24 [M+H]

Method Q Example 105:5-[(1-Cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(methylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(I-504)

To a 2 mL vial was charged1-(4-aminophenyl)-5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(9.8 mg, 24 μmol), DMF (150 μL), N,N-diisopropylethylamine (21 μL, 120μmol), and methylsulfamoyl chloride (6 μL, 72 μmol). The vial was sealedand heated at 50° C. for 2 h. Additional methylsulfamoyl chloride (6 μL,72 μmol) was added, and the contents of the vial were heated at 50° C.overnight. The reaction was cooled, quenched with methanol (100 μL), andconcentrated. The crude material was purified by mass triggeredpreparative HPLC (Method 6) to yield5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[(methylsulfamoyl)amino]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (singleton g, 1.0mg, 8%). LCMS: (ESI) m/z 502.23 [M+H].

Method T Example 106

A 100-mL round-bottom flask was charged with TFA salt of1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1 mmol), N,N-diisopropylethylamine (1.60 mmol),dichloromethane (10 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (1.3 mmol), 1-hydroxybenzotriazole (1.3 mmol) and theacids (1.2 mmol). The resulting solution was stirred for 4 h at 23° C.The mixture was then quenched by the addition water (10 mL). Theresulting solution was extracted with dichloromethane (3×20 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bypre-TLC eluting with 20/1-5/1 dichloromethane/methanol (20:1 v/v) togive desired product as a white or yellow solid.

Method U Example 107:1-(4-[4-[2-(benzyloxy)ethoxy]-1H-pyrazol-1-yl]phenyl)-5-([4-hydroxy-1-[(4-methylphenyl)carbonyl]piperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

A 50-mL 3-necked round-bottom flask fitted with a nitrogen inlet,magnetic stir bar, condenser and thermometer was charged with1-(4-bromophenyl)-5-([4-hydroxy-1-[(4-methylphenyl)carbonyl]piperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(130 mg, 0.25 mmol), cuprous iodide (2.5 mg, 0.01 mmol), 1,4-dioxane (20mL), potassium carbonate (75.4 mg, 0.54 mmol),4-[2-(benzyloxy)ethoxy]-1H-pyrazole hydrochloride (76 mg, 0.30 mmol) and(1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (7.4 mg, 0.05 mmol). Theresulting solution was stirred for 16 h at 110° C. in an oil bath undernitrogen. After cooling to 25° C., the reaction was quenched withsaturated ammonium chloride (10 mL). The product was extracted withethyl acetate (3×20 mL) and the organic layers combined. The organiclayer was washed with brine (20 mL), dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by preparatoryTLC plate eluting with dichloromethane/ethyl acetate (1:1 v/v) to give1-(4-[4-[2-(benzyloxy)ethoxy]-1H-pyrazol-1-yl]phenyl)-5-([4-hydroxy-1-[(4-methylphenyl)carbonyl]piperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(50 mg, 30%) as a yellow solid. LCMS: (ESI) m/z 660 [M+H].

Method V Example 108:Methyl-4-(5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoate

Step 4. Methyl4-(5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoate

A 25-mL round-bottom flask fitted with a magnetic stir bar was chargedwith4-[5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-4-oxo1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoicacid ((prepared according to procedure outlined in Example 40× utilizing6-[(4-fluorophenyl)carbonyl]-1-oxa-6-azaspiro[2.5]octane and4-(4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoic acid asstarting materials) (49.1 mg, 0.10 mmol), cesium carbonate (65.2 mg,0.20 mmol) and N,N-dimethylformamide (5 mL) followed by iodomethane(28.4 mg, 0.20 mmol) added dropwise. The resulting solution was stirredfor 2 h at 25° C. and quenched with water (20 mL). The product wasextracted with ethyl acetate (5×20 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was washed with water (5 mL) anddried in an oven to affordmethyl-4-(5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)benzoate(46.5 mg, 92%). LCMS: (ESI) m/z 506 [M+H].

Method Y Example 109:5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Enantiomer A-1-301) and5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Enantiomer B-1-302)

Step 1.5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar andthermometer was charged with ditrichloromethyl carbonate (148 mg, 0.50mmol), dichloromethane (50 mL), 2-benzylazetidine hydrochloride (183 mg,1.24 mmol). To the reaction was added N,N-diisopropylethylamine (387 mg,2.99 mmol) dropwise at 0° C. The resulting solution was stirred for 2 hat 0° C. before adding the TFA salt of1-(4-fluorophenyl)-5-[(4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(343 mg, 1.00 mmol) and N,N-diisopropylethylamine (387 mg, 2.99 mmol) indichloromethane (50 mL) dropwise at 0° C. After addition, the solutionwas stirred for 3 h at 0° C. and diluted with water (30 mL). The productwas extracted with dichloromethane (3×30 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparatory HPLC*to give5-([1-[(2-benzylazetidin-1-yl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1-(4-fluorophenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneas a white solid (200 mg, 39%). LCMS: (ESI) m/z 517 [M+H]. *Column:Xbridge Prep C₁₈ OBD, 19×150 mm, 5 m. Mobile phase A: aqueous ammoniumbicarbonate (0.05%)/Mobile phase B: acetonitrile. Gradient: 48% B to 53%B over 8 min. Detector: 220 and 254 nm.

Step 2.5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

The enantiomers were separated by SFC* to give5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,enantiomer A (I-301) (29.5 mg, 15%, stereochemistry unconfirmed). ¹H-NMR(300 MHz, DMSO-d₆) δ 1.30-1.62 (m, 4H), 1.76-1.95 (m, 1H), 1.98-2.15 (m,1H), 2.65-2.83 (m, 1H), 2.89-3.17 (m, 3H), 3.41-3.69 (m, 3H), 3.79-3.93(m, 1H), 4.02 (s, 2H), 4.32-4.59 (m, 1H), 4.90 (brs, 1H), 7.17-7.22 (m,3H), 7.29 (t, J=7.5 Hz, 2H), 7.40-7.46 (m, 2H), 8.05-8.10 (m, 2H), 8.35(s, 1H), 8.38 (s, 1H). LCMS: (ESI) m/z 517 [M+H] and5-((1-(2-benzylazetidine-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,enantiomer B (I-302) (29.5 mg, 15%, stereochemistry unconfirmed). ¹H-NMR(300 MHz, DMSO-d₆) δ 1.30-1.62 (m, 4H), 1.76-1.95 (m, 1H), 1.98-2.15 (m,1H), 2.69-2.79 (m, 1H), 2.91-3.13 (m, 3H), 3.41-3.65 (m, 3H), 3.82-3.91(m, 1H), 4.02 (s, 2H), 4.32-4.59 (m, 1H), 4.90 (brs, 1H), 7.17-7.22 (m,3H), 7.29 (t, J=7.2 Hz, 2H), 7.40-7.46 (m, 2H), 8.05-8.10 (m, 2H), 8.35(s, 1H), 8.38 (s, 1H). LCMS: (ESI) m/z 517 [M+H]. *Column: Chiralpak IC,2×25 cm, 5 μm. Mobile Phase A: methanol/Mobile Phase B: dichloromethane.Flow rate: 17 mL/min. Gradient: 10% B to 100% B over 11 min. Detector:254 and 220 nm. RT₁: 7.93 min; RT₂: 9.40 min.

Method Z Example 110:5-((4-Hydroxy-1-(4-(4-hydroxycyclohexyloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (I-1141)

A 100-mL round-bottom flask was charged with5-((1-(4-(4-(tert-butyldimethylsilyloxy)cyclohexyloxy)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (prepared by Step 1: procedure outlined in Method A utilizing5-((4-hydroxypiperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 4-hydroxybenzoic acid. Step 2: Procedure outlined inExperiment 172 utilizing4-[(tert-butyldimethylsilyl)oxy]cyclohexan-1-ol) (50 mg, 0.07 mmol),tetrahydrofuran (5 mL) and tetrabutylammonium fluoride intetrahydrofuran (1M, 1.5 mL). The resulting solution was stirred for 5 hat 40° C. in an oil bath. Upon cooling to 23° C., the reaction wasquenched with water (20 mL). The product was extracted with ethylacetate (5×10 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by preparative-HPLC* to afford5-((4-hydroxy-1-(4-(4-hydroxycyclohexyloxy)benzoyl)piperidin-4-yl)methyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.4 mg, 6%) as an off-white solid. 1H NMR (300 MHz, CDCl₃) δ1.23-1.45 (m, 5H), 1.57-1.64 (m, 5H), 1.81-1.85 (m, 2H), 1.99-2.01 (m,1H), 2.38 (s, 3H), 3.16-3.31 (m, 2H), 3.50-3.62 (m, 2H), 4.06 (s, 2H),4.36-4.60 (m, 2H), 4.98 (brs, 1H), 6.95-6.98 (m, 2H), 7.31-7.33 (m, 2H),7.38 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 8.33 (s, 1H), 8.34 (s,1H). LCMS: (ESI) m/z 558 [M+H]. *Column: X Bridge RP, 19×150 mm, 5 μm.Mobile phase A: aqueous ammonium bicarbonate (10 mM)/Mobile phase B:acetonitrile. Gradient: 15% B to 71% B over 7 min. Flow rate: 20 mL/min.Detector: 254 and 220 nm.

Method AA Example 111:5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,isomer A and isomer B

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(4-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(51 mg, 0.12 mmol), 4-methoxycyclohexyl methanesulfonate (25 mg, 0.12mmol), potassium carbonate (34 mg, 0.25 mmol) and N,N-dimethylformamide(10 mL). The resulting solution was stirred for 24 h at 80° C. in an oilbath. After cooling to 23° C., the reaction was then quenched by theaddition of water (20 mL). The resulting mixture was extracted withethyl acetate (3×30 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by preparatory HPLC* to give the racemic mixture(15 mg, 23%). LCMS: (ESI) m/z 536[M+H]. *Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm. Mobile phase A: aqueous ammonium hydroxide(0.05%)/Mobile phase B: acetonitrile. Flow rate: 20 mL/min. Gradient:25% B to 55% B in 7 min. Detector: 220 and 254 nm. The mixture (15 mg)was separated by chiral IIPLC** to give5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,isomer A (2.1 mg, 3%). ¹H-NMR (300 MHz, CD₃OD) δ 0.56-0.64 (m, 2H),0.85-0.89 (m, 2H), 1.25-1.28 (s, 4H), 1.48-1.58 (m, 2H), 1.60-1.96 (m,10H), 3.27-3.36 (m, 4H), 4.05-4.16 (m, 4H), 4.42-4.75 (m, 2H), 7.06 (d,J=9.0 Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.26 (s, 1H). LCMS:(ESI) m/z 536[M+H], and5-((4-Hydroxy-1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)methyl)-1-(4-((4-methoxycyclohexyl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, isomer B (2.1 mg,3%). ¹H-NMR (400 MHz, CD₃OD) δ 0.56-0.63 (m, 2H), 0.85-0.89 (m, 2H),1.26-1.28 (m, 4H), 1.38-1.72 (m, 8H), 2.01-2.15 (m, 4H), 3.05-3.35 (m,4H), 4.07-4.47 (m, 4H), 4.36-4.43 (m, 1H), 4.52-4.56 (m, 1H), 7.05 (d,J=9.0 Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.26 (s, 1H). LCMS:(ESI) m/z 536[M+H].

**Column: Chiralpak IC Column, 5 μm, 2×25 cm. Mobile Phase: methanol(0.1% diethylamine). Flow rate: 18 mL/min over 24 min. Detector: 254 and220 nm. RT₁: 16.2 min; RT₂: 20.5 min. #A similar method can be used foralkylation where the starting material is an epoxide such as1,5-dioxaspiro[2.3]hexane and5-(diphenylmethyl)-1-oxa-5-azaspiro[2.3]hexane (readily prepared fromthe corresponding ketone and trimethylsulfoxonium iodide)

Method AB Example 112.5-((1-(2′-aminobiphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-ethynylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 5-mL microwave tube fitted with a magnetic stir bar was charged with5-((1-(2′-aminobiphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-bromophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(prepared according to the procedure outlined in Method A, utilizing1-(4-bromophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneand 4-(2-aminophenyl)benzoic acid as starting materials) (100 mg, 0.17mmol), dioxane (2 mL), tributyl(ethynyl)stannane (64.5 mg, 0.20 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (12.4 mg, 0.02 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (16.2 mg,0.03 mmol). The resulting solution was irradiated with a microwave for 1h at 160° C. After cooling to 25° C., the reaction mixture was pouredinto water (20 mL). The product was extracted with ethyl acetate (5×20mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with petroleum ether/ethylacetate (7:1, v/v) to afford5-((1-(2′-aminobiphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-ethynylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneas a yellow oil (40 mg, 44%). LCMS: (ESI) m/z 545 [M+H].

Method M Example 113:5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(I-843)

Step 1. Tert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

A 50-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with1-(4-bromophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(500 mg, 1.06 mmol), Pd(dppf)Cl₂ (76 mg, 0.10 mmol), 1,4-dioxane (20mL), water (2 mL), potassium carbonate (440 mg, 3.18 mmol) and1-tert-butyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4,7,8-tetrahydro-2H-1-3,3-oxazocin-2-one(393 mg, 1.27 mmol). The solution was stirred for 8 h at 100° C. andcooled to 25° C. The resulting solution was diluted with water (30 mL)and the product was extracted with dichloromethane (3×20 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparative TLCeluting with dichloromethane/methanol (50:1, v/v) to afford tert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylateas a yellow oil (0.45 g, 65%). LCMS: (ESI) m/z 575 [M+H].

Step 2.Tert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)piperidine-1-carboxylate

A 100-mL round-bottom flask fitted with a hydrogen balloon and magneticstir bar was charged withtert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(Step 1, 400 mg, 0.69 mmol), palladium on carbon (0.1 g, 10%) andN,N-dimethylformamide (20 mL). The solution was stirred for 3 h at 25°C. under hydrogen. The solids were removed by filtration and thefiltrate was concentrated under vacuum to affordtert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)piperidine-1-carboxylate(0.37 g). LCMS: (ESI) m/z 577 [M+H].

Step 3.5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

The title compound was prepared according to the procedure outlined inExample 2 utilizingtert-butyl4-(4-(5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)phenyl)piperidine-1-carboxylate(Step 2, 400 mg, 0.69 mmol), as starting material and it was furtherpurified by preparatory HPLC* (15 mg, 18%). ¹H-NMR (300 MHz, CD₃OD) δ0.72-0.92 (m, 4H), 1.57-1.83 (m, 6H), 1.87-2.01 (m, 3H), 2.84-2.87 (m,3H), 3.08-3.24 (m, 3H), 3.52-3.59 (m, 1H), 4.01-4.23 (m, 4H), 7.45 (d,J=8.4 Hz, 2H), 8.00 (d, J=8.1 Hz, 2H), 8.25 (s, 1H), 8.33 (s, 1H). LCMS:(ESI) m/z 477 [M+H]. *Column, SunFire Prep C18, 19×150 mm. Mobile phaseA: aqueous ammonium bicarbonate (0.05%)/Mobile phase B: acetonitrile.Flow rate: 20 mL/min. Gradient: 40% B to 60% B over 8 min. Detector: 254and 220 nm.

Method AD Example 114:4-{[1-(4-fluorophenyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}-4-hydroxy-N-methylpiperidine-1-carboxamide(I-284)

A 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar andthermometer was charged with the1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneTFA salt (Intermediate 2-28, 95 mg, 0.21 mmol), dichloromethane (100 mL)and triethylamine (65 mg, 0.64 mmol). The reaction was treated withN-methylcarbamoyl chloride (45 mg, 0.48 mmol) in dichloromethane (1 mL)added in portions at 0° C. The resulting solution was warmed to 23° C.and stirred for 2 h. The reaction was quenched with water (20 mL) andthe product was extracted with dichloromethane (3×30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparatory HPLC*to give4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxy-N-methylpiperidine-1-carboxamide(16.5 mg, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.57 (m, 4H), 2.54-2.59(m, 3H), 2.95-3.05 (m, 2H), 3.54-3.68 (m, 2H), 4.02 (s, 2H), 4.86 (s,1H), 6.33-6.41 (m, 1H), 7.39-7.51 (m, 2H), 8.01-8.12 (m, 2H), 8.34 (s,1H), 8.38 (s, 1H). LCMS: (ESI) m/z 401 [M+H]. *Column: XBridge Prep C18OBD Column, 5 μm, 19×150 mm. Mobile phase A: aqueous ammoniumbicarbonate (0.05%)/Mobile phase B: acetonitrile. Flow rate: 20 mL/min.Gradient: 25% B to 66% over 10 min. Detector: 220 and 254 nm.

Method AE Example 115:5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-{4-[4-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(I-975)

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with1-(4-bromophenyl)-5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(100 mg, 0.21 mmol), 1-methyl-4-(1H-pyrazol-4-yl)piperazine (35 mg, 0.21mmol), potassium carbonate (8.77 mg, 0.06 mmol), 1,4-dioxane (20 mL),(1S,2S)-cyclohexane-1,2-diamine (2.4 mg, 0.02 mmol) and cuprous iodide(4 mg, 0.02 mmol). The resulting solution was stirred for 16 h at 110°C. in an oil bath. After cooling to 25° C., the reaction was quenchedwith water (30 mL). The product was extracted with ethyl acetate (3×30mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with dichloromethane/methanol(1:1, v/v). The product was further purified by preparative HPLC* toafford5-[(1-cyclopropanecarbonyl-4-hydroxypiperidin-4-yl)methyl]-1-[4-[4-(4-methylpiperazin-1-yl)-1H-pyrazol-1-yl]phenyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-oneas a white solid (8.7 mg, 7%) ¹H NMR (300 MHz, DMSO-d₆) δ 0.66-0.71 (m,4H), 1.40-1.60 (m, 4H), 1.95-1.99 (m, 1H), 2.23 (s, 3H), 2.44-2.48 (m,4H), 2.98-3.01 (m, 5H), 3.35-3.42 (m, 1H), 3.99-4.10 (m, 4H), 4.98 (brs,1H), 7.61 (s, 1H), 7.95 (d, J=9.0 Hz, 2H), 8.10 (s, 1H), 8.13 (d, J=9.0Hz, 2H), 8.38 (s, 1H), 8.39 (s, 1H). LCMS: (ESI) m/z 558 [M+H]. *Column:XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm. Mobile phase A: aqueousammonium bicarbonate (10 mmol/L)/Mobile phase B: acetonitrile. Gradient:18% B to 38% B over 8 min. Flow rate: 20 mL/min. Detector: 254 and 220.

Method AF Example 116:5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,enantiomer A (I-995) and5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,enantiomer B (I-996)

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylthio)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(100 mg, 0.20 mmol), dichloromethane (15 mL) and mCPBA (34.4 mg, 0.20mmol). The resulting solution was stirred at 0° C. for 10 min and thenquenched with water (10 mL). The product was extracted withdichloromethane. (3×10 mL) and the combined organic layers were washedwith brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparatory HPLC*to give5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one as a white solid (60 mg,58%). LCMS: (ESI) m/z 510 [M+H]. *Column: XBridge Prep C18 OBD Column, 5μm, 19×150 mm. Mobile phase A: aqueous ammonium bicarbonate(0.05%)/Mobile phase B: acetonitrile. Flow rate: 20 mL/min. Gradient:25% to 50% B over 8 min Detector: 220 and 254 nm.5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(122 mg, 0.24 mmol) was separated by **Chiral preparatory HPLC to give5-((I-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, enantiomer A (I-995)(36.3 mg, 30%) and5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfin-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneenantiomer B (I-996) (38.9 mg, 32%). A: ¹H NMR (400 MHz, CD₃OD) δ1.48-1.80 (m, 4H), 2.86 (s, 3H), 3.43-3.48 (m, 3H), 4.18 (s, 2H),4.33-4.35 (m, 1H), 7.17-7.22 (m, 2H), 7.45-7.50 (m, 2H), 7.88 (d, J=8.8Hz, 2H), 8.29 (s, 1H), 8.36 (s, 1H), 8.43 (d, J=8.8 Hz, 2H). B: ¹H NMR(400 MHz, CD₃OD) δ 1.48-1.82 (m, 4H), 2.86 (s, 3H), 3.43-3.56 (m, 3H),4.18 (s, 2H), 4.32-4.35 (m, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 8.29 (s, 1H), 8.37 (s, 1H), 8.43 (d,J=8.8 Hz, 2H). LCMS: (ESI) m/z 510 [M+H]. **Column: Chiralpak IC, 2×25cm, 5 μm. Mobile Phase: methanol over 45 min. Detector: 220 and 254 nm.RT₁: 9.33 min; RT₂: 6.22 min.

Method AG Example 117:5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,enantiomer A(I-997) and5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,enantiomer B(I-998)

Step 1.2,2,2-Trifluoro-N-([4-[5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzene](methane)sulfinylidene)acetamide

A 50-mL 3-necked round-bottom flask fitted with a magnetic stir bar,condenser and thermometer was charged with5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(methylsulfinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Example 116, 102 mg, 0.20 mmol), dichloromethane (20 mL), MgO (32 mg,0.80 mmol), rhodium acetate dimer (3.8 mg, 0.02 mmol) andtrifluoroacetamide (45.2 mg, 0.40 mmol) followed by iodobenzenediacetate (128 mg, 0.40 mmol) at 40° C. The resulting solution wasstirred for 16 h and concentrated under vacuum. The residue was purifiedby preparative thin layer chromatography eluting withdichloromethane/methanol (20:1, v/v) to afford2,2,2-trifluoro-N-([4-[5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzene](methane)sulfinylidene)acetamideas a yellow solid (82 mg, 66%). LCMS: (ESI) m/z 621 [M+H].

Step 2.5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

A 50-mL round-bottom flask fitted with a magnetic stir bar was chargedwith2,2,2-trifluoro-N-([4-[5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-1-yl]benzene](methane)sulfinylidene)acetamide(Step 1, 124 mg, 0.20 mmol), methanol (10 mL) and potassium carbonate(83 mg, 0.60 mmol). The resulting solution was stirred for 2 h at 27° C.The solids were removed by filtration and the filtrate was concentratedunder vacuum. The residue was purified by preparative thin layerchromatography eluting with dichloromethane/methanol (20:1, v/v) toafford the title compound (95 mg, 91%). LCMS: (ESI) m/z 525 [M+H].

Step 3. Chiral separation of5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(70 mg) was separated by **Chiral preparatory HPLC to give(5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,enantiomer A (I-997) (23.0 mg, 33%) and enantiomer B (I-998)5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(S-methylsulfonimidoyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(22.0 mg, 33%). Enantiomer A: ¹H NMR (300 MHz, CD₃OD) δ 1.30-1.68 (m,4H), 3.29 (s, 3H), 3.44-3.53 (m, 3H), 4.09 (s, 2H), 4.22-4.24 (m, 1H),7.12 (t, J=2.7 Hz, 2H), 7.36-7.42 (m, 2H), 8.11 (d, J=7.2 Hz, 2H), 8.22(s, 1H), 8.29 (s, 1H), 8.49 (d, J=9.0 Hz, 2H). 0B: ¹H NMR (300 MHz,CD₃OD) δ 1.39-1.68 (m, 4H), 3.14 (s, 3H), 3.30-3.45 (m, 3H), 4.08 (s,2H), 4.21-4.23 (m, 11H), 7.10 (t, J=8.7 Hz, 2H), 7.36-7.41 (m, 2H), 8.11(d, J=9.0 Hz, 2H), 8.21 (s, 1H), 8.28 (s, 1H), 8.41 (d, J=8.7 Hz, 2H).LCMS: (ESI) m/z 525 [M+H]. **Column: Repaired IA, 21.2×150 mm, 5 μm.Mobile Phase A: MTBE/Mobile Phase B: methanol. Gradient: 20% B to 30% Bover 24 min. Detector: 220 and 254 nm. RT₁: 13.917 min; RT₂: 20.080 min.

Method AH Example 118:2-(4-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetamide(I-1002)

Step 1.2-(4-(4-(4-((1-(4-Fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetonitrile

A 50-mL 3-necked round-bottom with fitted with a magnetic stir bar,condenser and thermometer was charged with5-((1-(4-(1H-pyrazol-4-yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(prepared according to the procedure outlined in Method A utilizing1-(4-fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-oneTFA salt and 4-(1H-pyrazol-4-yl)benzoic acid) (100 mg, 0.19 mmol),N,N-dimethylformamide (10 mL), 2-bromoacetonitrile (150 mg, 1.25 mmol)and cesium carbonate (500 mg, 1.53 mmol). The resulting solution wasstirred for 1 h at 120° C. After cooling to 23° C., the reaction wasquenched with water (20 mL) and the resulting mixture was extracted withethyl acetate (4×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography eluting withdichloromethane/methanol (50/1-20/1, v/v) to afford2-(4-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetonitrileas a yellow solid (80 mg, 74%). LCMS: (ESI) m/z 553 [M+H].

Step 2.2-(4-(4-(4-((1-(4-Fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetamide

A 100-mL round-bottom flask was charged with2-(4-(4-(4-((1-(4-fluorophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-1H-pyrazol-1-yl)acetonitrile(60 mg, 0.11 mmol), DMSO (20 mL), ethanol (10 mL), potassium carbonate(250 mg, 1.81 mmol) and hydrogen peroxide (5 mL, 30%). The resultingsolution was stirred for 1 h at 23° C. The reaction was quenched withsaturated aqueous sodium thiosulfate (20 mL). The product was extractedwith ethyl acetate (4×30 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by preparatory HPLC* to afford1-(4-fluoro-3-(hydroxymethyl)phenyl)-5-((4-hydroxy-1-(4-(pyrimidin-2-yloxy)benzoyl)piperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(10 mg, 9%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.30-1.55 (m, 2H), 1.56-1.71(m, 2H), 3.05-3.30 (m, 2H), 3.38-3.61 (m, 1H), 4.02-4.29 (m, 3H), 4.78(s, 2H), 5.00 (brs, 1H), 7.29 (s, 1H), 7.32-7.49 (m, 4H), 7.52 (s, 1H),7.64 (d, J=8.4 Hz, 2H), 7.95 (s, 1H), 8.01-8.11 (m, 2H), 8.19 (s, 1H),8.36 (s, 1H), 8.37 (s, 1H). LCMS: (ESI) m/z 571 [M+H]. *Column: XBridgePrep C18 OBD Column, 5 μm, 19×150 mm. Mobile phase A: aqueous ammoniumbicarbonate (0.05%)/Mobile phase B: acetonitrile. Flow rate: 20 mL/min.Gradient: 15% B to 48% B over 10 min. Detector: 220 and 254 nm.

Method AI Example 119:5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(1-methylpiperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(I-1007)

Step 1.(E)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(pyridin-2-yl)vinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 100-mL 3-necked round-bottom flask fitted with a nitrogen balloon,magnetic stir bar, condenser and thermometer was charged with1-(4-bromophenyl)-5-([1-[(4-fluorophenyl)carbonyl]-4-hydroxypiperidin-4-yl]methyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(200 mg, 0.38 mmol), 2-ethenylpyridine (210 mg, 2.00 mmol), palladiumacetate (30 mg, 0.13 mmol),(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (30 mg, 0.05 mmol),potassium acetate (113 mg, 1.15 mmol) and N,N-dimethylformamide (20 mL).The resulting solution was stirred for 10 h at 100° C. in an oil bathand cooled to 25° C. The reaction was quenched with water (40 mL). Theproduct was extracted with dichloromethane (3×40 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography eluting with ethyl acetate/petroleumether (10:1, v:v) to afford the title compound (100 mg, 48%). L CMS:(ESI) m/z 551 [M+H].

Step 2.5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(piperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 100-mL pressure tank reactor fitted with a magnetic stir bar wascharged with(E)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(pyridin-2-yl)vinyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Step 1, 150 mg, 0.27 mmol), methanol (20 mL) and platinum oxide (20 mg,0.05 mmol). The resulting solution was stirred for 12 h under hydrogen(0.8 MPa) at 23° C. The solids were removed by filtration and thefiltrate was concentrated under vacuum to afford the title compound (120mg). LCMS: (ESI) m/z 559 [M+H].

Step 3.5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(1-methylpiperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(2-(piperidin-2-yl)ethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Step 2, 50 mg, 0.09 mmol), a solution of formaldehyde in water (2 mL,37%), tetrahydrofuran (15 mL), sodium cyanoborohydride (17 mg, 0.3 mmol)and acetic acid (5 mg, 0.08 mmol). The solution was stirred for 2 h andconcentrated under vacuum. The crude mixture was purified by preparatoryHPLC* to afford the title compound (20 mg, 39%). ¹H NMR (300 MHz,DMSO-d) δ 1.26-1.75 (m, 11H), 1.80-2.49 (m, 6H), 2.55-2.78 (m, 2H),2.91-3.33 (m, 4H), 4.06 (s, 2H), 4.07-4.18 (m, 1H), 5.03 (brs, 1H),7.24-7.30 (m, 2H), 7.40-7.49 (m, 4H), 7.91-7.94 (d, J=8.4 Hz, 2H), 8.34(s, 2H). LCMS: (ESI) m/z 573 [M+H]. *Column: X Bridge C18, 19×150 mm, 5μm. Mobile phase A: Water (0.05% ammonium bicarbonate)/Mobile phase B:acetonitrile. Flow rate: 20 mL/min. Gradient: 10% B to 80% B over 10min). Detector: 220 and 254 nm.

Method AK Example 120Syn-5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,isomer A (I-1039a); andAnti-5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,isomer B (I-1039B)

A 100-mL round-bottom flask fitted with a magnetic stir bar was chargedwith5-((4-hydroxy-1-(4-oxocyclohexanecarbonyl)piperidin-4-yl)methyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(220 mg, 0.5 mmol), dichloromethane (20 mL), 2-fluoropyridin-3-amine (70mg, 0.6 mmol) and sodium triacetoxyborohydride (300 mg, 1.42 mmol). Theresulting mixture was stirred for 1 h at 23° C. The reaction wasquenched with water (30 mL) and the product was extracted withdichloromethane (4×20 mL). The combined organic layers were washed withbrine (30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparatory HPLC*to afford5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,isomer A (I-1039a); (12.5 mg, 5%). ¹H-NMR (300 MHz, DMSO-d₆) δ 1.22-1.78(m, 10H), 1.90-1.99 (m, 2H), 2.56-2.63 (m, 1H), 2.87-3.01 (m, 1H),3.17-3.30 (m, 2H), 3.65-3.76 (m, 1H), 4.01-4.16 (m, 3H), 5.02 (brs, 1H),5.46 (d, J=8.1 Hz, 1H), 7.05-7.09 (m, 1H), 7.13-7.19 (m, 1H), 7.25-7.32(m, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 2H), 8.07 (d, J=8.1Hz, 2H), 8.37 (s, 1H), 8.38 (s, 1H). LCMS: (ESI) m/z 546[M+H] and5-((1-(4-((2-fluoropyridin-3-yl)amino)cyclohexane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,isomer B (I-1039b) (30.7 mg, 11%). ¹H-NMR (300 MHz, DMSO-d₆) δ 1.35-1.88(m, 12H), 2.67-2.78 (m, 1H), 2.87-3.01 (m, 1H), 3.17-3.30 (m, 1H),3.48-3.58 (m, 1H), 3.67-3.75 (m, 1H), 3.95-4.16 (m, 3H), 4.98 (brs, 1H),5.24 (d, J=5.7 Hz, 1H), 7.06-7.15 (m, 2H), 7.28-7.32 (m, 1H), 7.43 (t,J=7.5 Hz, 1H), 7.59 (t, J=8.1 Hz, 2H), 8.07 (d, J=7.8 Hz, 2H), 8.36 (s,1H), 8.39 (s, 1H). LCMS: (ESI) m/z 546[M+H]. *Column: XBridge Prep C18OBD Column, 5 μm, 19×150 mm. Mobile phase A: water (0.1% FA)/Mobilephase B: acetonitrile. Flow rate: 20 mL/min. Gradient: 18% B to 57% over12.5 min. Detector: 220 and 254 nm.

Method AL Example 121:1-(3-((3,3-difluorocyclobutyl)methoxy)phenyl)-5-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-1046)

A 100-mL 3-necked round-bottom fitted with a magnetic stir bar condenserand thermometer was charged with5-([4-hydroxy-1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl]methyl)-1-(3-hydroxyphenyl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one(320 mg, 0.68 mmol), N,N-dimethylformamide (10 mL),(3,3-difluorocyclobutyl)methyl methanesulfonate (197 mg, 0.94 mmol) andpotassium carbonate (313 mg, 2.24 mmol). The resulting mixture wasstirred for 16 h at 120° C. in an oil bath. After cooling to 25° C., thereaction was quenched with water (20 mL). The resulting mixture wasextracted with ethyl acetate (3×30 mL) and the combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by preparative HPLC* to affordthe title compound (13 mg, 4%). ¹H-NMR (400 MHz, DMSO-d₆) δ 0.49-0.51(m, 2H), 0.74-0.77 (m, 2H), 1.19 (s, 3H), 1.39-1.42 (m, 2H), 1.50-1.55(m, 2H), 2.44-2.47 (m, 1H), 2.55-2.79 (m, 4H), 3.05-3.20 (m, 2H),3.94-3.98 (m, 2H), 4.03 (s, 2H), 4.10 (d, J=6.4 Hz, 2H), 4.94 (brs, 1H),6.98 (dd, J=1.6, 6.8 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.65-7.69 (m, 2H),8.34 (s, 1H), 8.35 (s, 1H). LCMS: (ESI) m/z 528[M+H]. *Column: XBridgePrep C18 OBD Column, 100 Å, 19×250 mm, 5 μm. Mobile phase A: 0.05%aqueous ammonium bicarbonate/Mobile phase B: acetonitrile. Gradient: 30%B to 41% B over 8 min. Flow rate: 20 mL/min. Detector: 254 and 220 nm.

Method AM Example 122:((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(I-770)

A 100-mL round-bottom flask fitted with a nitrogen balloon, magneticstir bar, condenser and thermometer was charged with1-(5-bromopyridin-2-yl)pyrrolidin-3-ol (Intermediate 2-7b, 85 mg, 0.35mmol),5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(Intermediate 2-149, 200 mg, 0.39 mmol), DMF (30 mL), water (3 mL),sodium carbonate (112 mg, 1.06 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.02mmol). The resulting solution was stirred for 5 h at 100° C. in an oilbath. After cooling to 23° C., the reaction was quenched by the additionof water (60 mL). The resulting mixture was extracted withdichloromethane (5×40 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was further purified by preparative HPLC* to afford5-((1-(cyclopropanecarbonyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(44 mg, 37%) as a light yellow solid. LCMS: (ES) m/z 556 [M+H]. ¹H-NMR(400 MHz, DMSO-d₆) δ 0.63-0.74 (m, 4H), 1.33-1.64 (m, 4H), 1.86-2.10 (m,3H), 2.92-2.99 (m, 1H), 3.30-3.42 (m, 2H), 3.43-3.55 (m, 3H), 3.91-4.23(m, 4H), 4.35-4.39 (m, 1H), 4.97 (brs, 2H), 6.54 (d, J=8.8 Hz, 1H), 7.79(d, J=8.8 Hz, 2H), 7.88 (dd, J=2.8, 8.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H),8.36 (s, 1H), 8.37 (s, 1H), 8.49 (s, 1H). *Column: XBridge Prep C18 5 μmOBD 19×150 mm. Mobile phase A: 0.05% aqueous ammoniumbicarbonate)/Mobile phase B: acetonitrile. Gradient: 30% B to 80% B over20 min. Flow rate: 20 mL/min. Detector: UV 254/220 nm.

Method N Example 123:(R)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(I-484)

A reaction vial was charged with1-(4-bromophenyl)-5-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(15.8 mg), and (R)-octahydro-2H-pyrido[1,2-a]pyrazine. The reaction vialwas flushed with nitrogen, and DMF,methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)was introduced. The vial was sealed and heated at 120° C. for 8 h. Thereaction mixture was concentrated, diluted with brine (500 μL), andextracted with ethyl acetate (2×500 μL). Purification by HPLC (Method 6)afforded the title compound. LCMS: (ES) m/z 586 [M+H]

Purification Example 124: Chiral and Diastereomers Purification andSeparation

The R and S enantiomers of racemic compounds and the diastereomers(including cis- and trans-) of compounds were separated using eitherChiral SFC or Chiral HPLC or preparative HPLC or SFC utilizing differentcolumns such as XBridge Shield RP18 OBD, (CHIRALCEL OJ, CHIRALCEL OD,ChiralPAK AD, (R,R)-WHELK-Ol-Kromasil, ChiralPAK IA, ChiralPAK IC,ChiralPAK ID, Lux Cellulose-4, SHIIADZU-SPD-20A, Phenomenex Lux,Cellulose-4, Anchintcq ACl Am-1 with different dimensions and diameter.

Columns were eluted with two mobile phases (Phase A and Phase B) withgradient from 0 to 100% for both phases. Some examples of phases usedbut not limited: 0.1% diethylamine in MeOH, water (0.05% TFA), MeCN,Hexane (0.1% diethylamine or diisopropylamine), MeOH, dichloromethane,isopropanol, ethanol, MTBE, 0.2% isopropanol in EtOH, 0.1% isopropanolin hexane, 0.1% aqueous diethyl amine, 0.1% or 0.2% 2,6-diethylanilinein tert butyl methyl ether. Peaks were detected at 220 and 254 nm.Biochemical Assays

Example 125: USP7 Assay A (Ubitquin-Rhodamine 110 Assay)

Each assay was performed in a final volume of 15 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-Glutathione reduced; Sigma #G4251),0.03% BGG (0.22 μM filtered, Sigma, #G7516-25G), and 0.01% Triton X-100(Sigma, #T9284-10L). Nanoliter quantities of either an 8-point or10-point, 3-fold serial dilution in DMSO was pre-dispensed into assayplates (Perkin Elmer, ProxiPlate-384 F Plus, #6008269) for a final testconcentration range of either 25 μM to 11 nM or 25 μM to 1.3 nM,respectively. The final concentration of the enzyme (USP7, constructUSP7 (208-1102) 6*His, Viva Biotech) in the assay was 62.5 μM. Finalsubstrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555)concentration was 25 nM with [Ub-Rh110]<<Km. 5 μL of 2× enzyme was addedto assay plates (pre-stamped with compound) preincubated with USP7 for30 minutes and then 5 μL of 2×Ub-Rh110 was added to assay plates. Plateswere incubated stacked for 20 minutes at room temperature before 5 μL ofstop solution (final concentration of 10 mM citric acid in assay buffer(Sigma, #251275-500G)). Fluorescence was read on the Envision(Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on thePheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Example 126: USP7 Assay B (Ubitquin-Rhodamine 110 Assay)

Each assay was performed in a final volume of 20 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 2 mM CaCl₂ (1M Calcium Chloride solution; Sigma#21114) 1 mM GSH (L-Glutathione reduced; Sigma #G4251), 0.01% Prionex(0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stockcompound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1month prior to the assay, 2 mM test compounds were pre-dispensed intoassay plates (Black, low volume; Corning #3820) and frozen at −20° C.Prestamped assay plates were allowed to come to room temperature on theday of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for afinal screening concentration of 10 μM (DMSO_((fc))=0.5%). For follow-upstudies, 250 nL of an 8-point, 3-fold serial dilution in DMSO waspre-dispensed into assay plates for a final test concentration of 25μM-11 nM (1.25% DMSO final concentration). Unless otherwise indicated,all follow-up assays were run on triplecate plates. Enzyme (USP7,construct Met (208-1102)-TEV-6*His; Viva Q93009-1) concentration andincubation times were optimized for the maximal signal-to-backgroundwhile maintaining initial velocity conditions at a fixed substrateconcentration. The final concentration of the enzyme in the assay waseither 75 μM or 250 μM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine110, R&D Systems (biotechne) #U-555) concentration was 25 nM with[Ub-Rh110]<<Km. Pre-stamped with compounds were either not preincubatedor preincubated with USP7 between 30 to 120 minutes prior to theaddition of 10 μL of 2×Ub-Rh110 to compound plates. Plates wereincubated stacked for either 23 or 45 minutes at room temperature beforefluorescence was read on the Envision (Excitation at 485 nm and Emissionat 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm andEmission at 535 nm; BMG Labtech).

Data from USP7 Assays A and B were reported as percent inhibition (inh)compared with control wells based on the following equation: %inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measuredFluorescence (See Tables 6-10). Ave_(Low)=average Fluorescence of noenzyme control (n=16). Ave_(High)=average Fluorescence of DMSO control(n=16). IC₅₀ values were determined by curve fitting of the standard 4parameter logistic fitting algorithm included in the Activity Basesoftware package: IDBS XE Designer Model 205. Data is fitted using theLevenburg Marquardt algorithm. IC₅₀ data from USP7 Assays A-B for thecompounds of the invention can be found in the Table below.

TABLE 37 USP7 activity of compounds of the invention in USP7 assay A andB. LCMS: HPLC (ESI) retention Compounds m/z time/ No.: Method [M + H]mins USP7_IC50 I-1024 AK 564 1.4734 ++++ I-1023 AK 564 1.3952 ++++I-1047 AL 542 1.4897 ++++ I-1046 AL 542 1.4357 +++ I-1016 A 562 0.9501+++ I-1022 A 562 1.1794 +++ I-1015 A 562 1.3548 +++ I-1037 A 584 1.5436++ I-1036 A 584 1.5542 ++++ I-1018 A 602 1.2874 ++++ I-1035 A 518 0.7317+++ I-1034 A 518 0.7343 ++ I-1033 A 536 0.9366 ++ I-1032 A 536 0.9096+++ I-1031 A 518 0.7292 +++ I-1030 A 518 0.7317 +++ I-1014 A, I 5721.4575 +++ I-1021 A, 548 1.2992 +++ I-1038 A, 546 1.2334 ++++ I-1042 A492 1.3042 +++ I-1020 A 559 1.3817 +++ I-1019 A 559 1.4217 +++ I-1039 AK546 1.2834 +++ I-1039b AK 546 1.3467 ++++ I-1041 AK 548 0.89 +++ I-1040AK 548 0.8933 ++ I-1017 A 547 1.3283 +++ I-1112 A 520 1.375 ++ I-926 A554 1.2733 +++ I-925 A 554 1.175 ++ I-1212 A 548 1.1083 +++ I-1113 A 5481.2783 ++++ I-794 A 549 1.1617 +++ I-1114 A 549 1.1833 ++ I-1167 A 5501.455 ++ I-1166 A 550 1.46 ++++ I-807 AK 550 1.2017 ++ I-806 AK 5501.2333 +++ I-1067 A 549 1.1933 +++ I-791 A 597 1.5683 +++ I-790 A 5971.5683 ++++ I-785 A 597 1.535 +++ I-784 A 597 1.5333 ++++ I-765 AK 5490.845 ++ I-1075 A, W 537 1.0933 ++ I-1124 A 546 1.2917 ++++ I-766 AK 5490.9167 +++ I-1116 AA 536 1.3033 +++ I-815 AA 536 1.2967 +++ I-924 A, W537 0.9783 ++ I-1029 A 498 1.2117 ++ I-1028 A 498 1.2083 ++++ I-1445 N509 1.1583 +++ I-1561 N 509 1.2233 ++++ I-1570 N 547 1.2283 +++ I-1732 N547 1.2833 +++ I-764 AK 549 0.91 +++ I-763 AK 549 0.8283 ++ I-748 A 5481.166 +++ I-747 A 548 1.2083 ++ I-1728 N 527 1.3143 +++ I-1675 N 5271.3433 ++++ I-1674 N 521 1.0417 +++ I-1676 N 521 1.0933 ++++ I-1677 N479 0.8767 +++ I-1678 N 479 0.9232 +++ I-1679 N 481 1.1433 +++ I-1680 N481 1.1867 +++ I-1636 N 548 0.6033 +++ I-1637 N 548 0.6317 +++ I-742 A547 1.4783 +++ I-741 A 547 1.4867 ++++ I-789 A 601 1.2383 ++++ I-788 A601 1.2367 ++ I-1126 A 533 1.2874 ++++ I-1125 A 533 1.2883 +++ I-1638 N534 0.6067 ++++ I-1639 N 520 0.5883 ++++ I-1640 N 520 0.5883 ++++ I-1641N 506 0.565 ++++ I-1642 N 547 0.8717 +++ I-1643 N 505 1.025 +++ I-1644 N532 0.6467 ++++ I-1645 N 534 0.6383 ++++ I-1646 N 520 0.6183 ++++ I-1689N 520 0.6167 ++++ I-1690 N 506 0.595 ++++ I-1691 N 547 0.96 +++ I-1692 N505 1.07 ++++ I-1693 N 556 0.695 +++ I-1694 N 556 0.7217 ++++ I-1079 A477 1.065 +++ I-1078 A 451 0.977 +++ I-1077 A 452 1.0183 +++ I-744 A 5471.4367 +++ I-743 A 547 1.4433 ++ I-793 A 595 0.6433 ++++ I-792 A 5950.6417 +++ I-746 A 561 1.4517 ++ I-745 A 561 1.4333 ++ I-740 A 5651.5083 +++ I-739 A 565 1.5167 ++++ I-738 A 565 1.4733 +++ I-737 A 5651.4783 ++++ I-752 A 547 0.74 ++++ I-751 A 547 0.8433 ++ I-1695 A 4530.9433 ++++ I-1696 A 453 0.9433 + I-736 A 530 1.27 + I-735 A 530 1.27 ++I-734 A 550, 552 1.3733 + I-733 A 550, 552 1.3683 +++ I-732 A 550, 5521.3667 ++ I-731 A 550, 552 1.3683 ++++ I-728 H, W, A 534 1.1683 +++I-727 H, W, A 534 1.2383 +++ I-1697 A 454 0.8917 ++++ I-1698 A 4540.8917 + I-1700 N 548 0.62 +++ I-1701 N 548 0.5933 +++ I-1702 N 5460.9517 +++ I-1747 N 546 0.9117 +++ I-1748 N 546 0.9533 +++ I-1749 N 5460.9117 +++ I-1750 N 550 0.6283 +++ I-1751 N 516 1.155 +++ I-1752 N 5161.1083 +++ I-797 A 530 1.37 ++ I-796 A 530 1.37 ++++ I-786 N 541 1.3067+++ I-760 Y 517 1.4762 ++ I-759 Y 517 1.4767 ++ I-768 AK 545 1.1033 ++++I-767 AK 545 0.935 +++ I-758 A 550 1.16 +++ I-757 A 550 1.17 +++ I-855AK, K, 567 0.5967 ++++ Example 2, A I-1133 AA 528 1.4 ++++ I-770 Example2, 581 1.39 ++++ A, S, AA I-1072 A, AK 509 0.7342 ++ I-769 A, AK 5090.685 +++ I-756 A 551 1.355 +++ I-755 A 551 1.335 +++ I-853 A, J 5591.03 +++ I-852 A, J 559 0.9383 ++++ I-1163 A 556 1.325 ++ I-1162 A 5561.3233 ++++ I-1753 A 454 0.8983 +++ I-1754 AE 492 1.2583 +++ I-1710 AE488 1.185 +++ I-1711 A, AE 504 1.0683 ++ I-799 A 475 1.2167 +++ I-981 A,S, AA 563 1.36 ++++ I-1508 A, S, AA 559 1.6483 +++ I-771 A 510 1.1817+++ I-846 A 489 1.3952 +++ I-783 A 535 1.2334 +++ I-1135 A, S, AA 5371.2717 ++++ I-772 A 468 1.1308 +++ I-762 AH, Example 2, D 507 1.058 ++I-725 A 506 1.058 ++ I-761 D 493 0.6767 ++++ I-798 A 500 1.2603 +++I-754 A 550 1.2 +++ I-753 A 550 1.2175 +++ I-750 A 547 0.8817 +++ I-749A 547 0.8417 ++++ I-1025 A 556 1.3278 +++ I-1716 N 533 0.9467 ++++I-1717 AE 556 1.5436 ++++ I-1043 AE 542 1.4357 +++ I-1045 AE 508 1.3548++++ I-724 A 492 0.95 +++ I-1136 A, S, AA 523 1.245 ++++ I-1118 A, S, AA508 1.1333 ++++ I-923 AA 552 1.14 ++ I-835 A 598 1.08 ++++ I-847 A 5161.5075 +++ I-726 A 478 1.085 +++ I-1137 A, S, AA 524 1.4842 ++++ I-1119S, AA 510 1.3792 ++++ I-840 A 562 0.9906 ++ I-839 A 562 0.9906 ++++I-838 A 562 0.9906 ++ I-837 A 562 0.9906 ++++ I-836 A 598 1.0825 ++I-834 A 598 1.085 ++ I-833 A 598 1.745 ++++ I-1718 N 581 1.4917 ++++I-490 N 567 1.375 +++ I-1719 H 572 1.1983 ++++ I-1720 H 528 1.2733 ++++I-1721 H 538 1.3267 ++++ I-1722 H 558 1.0933 ++++ I-1723 H 514 1.1617+++ I-489 H 524 1.22 +++ I-781 A 474 1.1242 +++ I-782 A 488 1.2358 ++++I-780 AE, Example 2, A 527 1.1242 ++++ I-778 N, Example 2, A 547 0.6264++++ I-777 N, Example 2, A 547 0.6264 ++++ I-822 A 582 0.9333 +++ I-821A 582 0.9232 ++ I-818 AE 559 0.6399 ++++ I-975 N, Example 2a, AE 5590.6128 +++ I-712 H 530 1.1367 ++ I-1117 A, S, AA 543 1.4583 +++ I-1134A, S, AA 569 1.3548 +++ I-776 H 541 1.031 ++++ I-775 H, Example 2, T 4881.031 +++ I-795 A, W, J 572 0.8675 ++ I-922 Y 552 1.3325 ++ I-1052 A 5620.9892 +++ I-819 AE 546 1.0392 +++ I-817 A, S, AA 595 1.4492 ++++ I-1110A 559 1.4357 ++++ I-987 U 528 0.6938 ++ I-988 U 528 0.68 ++ I-820 AE 5701.2064 +++ I-976 AE 571 1.19 ++ I-1681 N 572 0.74 ++ I-1682 N 572 0.73++ I-1683 N 586 0.76 ++ I-553 A 584 1.1792 +++ I-1096 A 577 0.84 ++I-672 R 571 1.1255 +++ I-1089 A 546 1.2675 +++ I-1684 AE 557 0.9092 ++++I-1685 AE 595 1.4342 ++++ I-1686 AE 561 1.3548 ++++ I-779 A 541 1.2317++++ I-1687 AE 531 0.8133 ++++ I-1688 AE 569 1.34 ++++ I-1733 AE 5351.2575 ++++ I-488 AE 515 1.1255 ++++ I-1734 AE 544 1.0175 +++ I-1735 N572 0.7333 ++ I-487 N 572 0.7343 ++ I-921 A 532 1.02 ++ I-557 A 529 1.39+++ I-1164 A 543 1.39 ++++ I-1161 A 542 1.24 ++++ I-687 L, AM 556 0.63+++ I-686 L, AM 556 0.63 +++ I-685 N, H, Example 2a 569 0.5 ++++ I-684N, H, Example 2a 569 0.5 ++++ I-977 AE, R 520 0.92 ++ I-985 N 538 0.77+++ I-920 I, A 564 0.8 ++ I-1736 H 510 1.2033 +++ I-1737 H 539 1.3526 ++I-1738 H 511 1.1567 ++ I-1739 N 533 0.7283 ++ I-1740 N 601 0.9486 +++I-1741 N 547 0.785 +++ I-699 N 580 1.32 +++ I-551 T 570 1.2 +++ I-543 A534 1.32 +++ I-542 A 534 1.32 ++++ I-1092 A 494 0.82 ++ I-673 AE 5291.08 ++ I-983 H 528 0.69 ++ I-984 H 542 0.69 ++ I-919 A 531 1.11 ++I-552 A 569 0.99 +++ I-549 A 520 1.21 ++ I-548 A 521 1.1933 ++ I-832 A,Example 2, A 561 0.48 ++++ I-561 A 545 1.53 +++ I-560 A 545 1.54 +++I-559 A 563 1.51 ++ I-558 A 545 1.53 +++ I-845 N, H, Example 2a 569 0.5++++ I-1093 A 494 1.31 ++ I-1091 A 496 1.33 ++ I-696 A, S, AA 550 1.49+++ I-692 A, S, AA, 533 0.66 ++++ I-1101 H 558 0.83 ++ I-1090 A 531 1.23+++ I-1744 H 646 1.14 +++ I-1745 H 618 1.18 +++ I-1746 H 554 1.29 +++I-1614 H 598 1.21 +++ I-1615 H 570 1.14 +++ I-1616 H 586 1.18 +++ I-1617H 586 1.14 +++ I-1095 A 494 1.2333 +++ I-556 A 480 1.17 ++ I-693 A, S,AA 580 1.31 +++ I-1099 H 558 0.83 ++ I-1087 A 532 1.27 +++ I-1621 A 6140.68 ++++ I-1622 A 560 0.56 ++++ I-1755 N 503 1.11 ++ I-1756 O 548 1.26+++ I-486 P 499 0.71 ++ I-612 A, AE 544 1.06 ++ I-613 AE, W, T, R 5430.71 ++ I-550 A 556 1.18 +++ I-546 A 548 1.3283 +++ I-545 A 547 1.24 +++I-544 A 547 1.24 ++ I-918 A 534 1.3 + I-1159 A 534 1.3 ++++ I-660 A,Example 2, B 553 1.38 +++ I-850 A 492 1.15 +++ I-849 A 478 1.13 ++++I-1010 A 508 0.6 ++ I-629 A 501 1.33 ++++ I-816 S, AA, R, AK 563 0.65++++ I-1088 A 530 0.81 +++ I-697 D, AA 586 0.91 + I-646 A 574 1.52 ++I-645 A 574 1.52 +++ I-1006 A, H, R 558 1.07 ++ I-1002 A, H, AH 571 1.02++ I-1001 A 569 0.72 ++ I-1000 A 569 0.72 ++ I-611 A 555 0.71 ++ I-917 A515 1.34 ++ I-1160 A 597 1.21 +++ I-831 A, Example 2, A 561 0.52 ++++I-1009 A 490 0.59 ++ I-830 A 596 0.64 +++ I-829 A 597 0.635 ++++ I-915 A538 0.96 ++ I-1140 A 493 1.4 +++ I-1086 A 548 1.22 ++ I-547 A 542 1.23++ I-610 Y 548 1.33 ++ I-827 A 596 0.6 ++ I-826 A 597 0.6117 ++++ I-825A 596 0.61 ++++ I-1132 A 532 1.33 +++ I-1131 A 532 1.33 ++ I-604 A 5580.72 ++ I-1005 A, Example 2 544 0.71 ++ I-643 A 582 1.36 +++ I-555 A 5241.04 +++ I-1764 H 524 1.29 ++ I-1768 H 510 0.65 +++ I-1725 H 485 0.79 ++I-1726 H 485 0.92 +++ I-554 A 497 1.33 ++ I-1085 A 553 0.76 ++ I-1108 A511 1.27 + I-912 A 534 1.27 ++ I-913 A 534 1.27 ++ I-1727 N 526 0.66 ++I-1729 N 580 0.77 ++ I-562 AA, W, A 544 1.22 ++ I-563 AA, T 545 1.35 ++I-1673 H 516 1 ++ I-1672 H 528 1.15 ++ I-603 A, R 528 1.16 ++++ I-1178 N570 1 ++ I-1176 N 584 1 ++ I-1170 N 569 0.71 +++ I-1168 N 547 1.14 +++I-1657 N 493 0.98 ++ I-1434 N 533 1.07 ++ I-1655 N 479 0.9 ++ I-1654 N569 1.05 +++ I-1632 N 442 1.29 ++ I-541 A 528 1.29 +++ I-1003 A, R, B495 1.01 ++ I-680 H, S, J 569 0.87 +++ I-679 H, S, J 569 0.87 ++++ I-484N 586 0.88 ++++ I-720 A 496 1.18 ++ I-1625 A 401 1.14 + I-1623 AE 5281.31 ++ I-690 N, AM, Example 2 568 0.88 +++ I-689 N, H, Example 2a 5680.76 ++++ I-842 H, AA, Example 2 555 0.85 +++ I-841 H, AA, Example 2 5550.85 +++ I-856 A, H, S, I 557 0.94 +++ I-972 K, Example 2, A, L 525 1.3++ I-971 K, Example 2, A, L 525 1.29 +++ I-719 A 544 1.2 ++ I-605 A, H,R, Example 545 0.89 + 2, AK I-911 T 530 1.09 ++ I-536 A 522 1.21 ++I-678 H, AA 569 0.87 +++ I-675 H, AA, Example 2 555 0.85 +++ I-601 W, T,AK 561 0.88 + I-1667 O 494 1.05 ++ I-1666 AE 497 1.26 + I-537 L, W, T564 0.89 ++ I-1129 A 531 1.4 ++ I-688 N, AM, Example 2 568 0.88 +++I-701 N 526 0.75 ++ I-633 N 525 1.3 ++ I-691 H, Example 2a 541 0.8 ++I-698 L, H, Example 2 554 0.95 +++ I-1659 A 537 1.44 +++ I-482 AD 4691.3 + I-1584 N 532 0.71 +++ I-535 A 514 1.21 +++ I-1128 A 531 1.22 +++I-970 N 546 0.8 ++ I-638 N 511 1.05 +++ I-637 N 511 1.05 +++ I-528 A 5601.27 ++ I-527 A 560 1.27 ++ I-634 N 546 0.81 ++ I-533 A 561 0.9 ++ I-657A, Example 2, B 539 1.29 +++ I-636 N 511 1.05 +++ I-529 AK, A 531 0.88++ I-1127 AK, A 547 1.03 ++ I-843 H, R, Example 2 477 0.69 +++ I-526 A560 1.27 ++ I-580 A, Example 2, B 495 1.01 +++ I-713 K, Example 10 5041.07 ++ I-525 A 523 0.98 + I-524 A 523 0.99 ++ I-1142 A, AA, Example 5290.94 ++ 2, AK I-1007 AI 573 0.92 ++ I-1576 AD 534 0.98 ++ I-1437 A 5291.36 ++ I-1526 AE 531 1.34 ++ I-508 N, Example 2a 549 0.69 +++ I-523 A523 0.98 + I-522 A 520 1.22 + I-521 A 520 1.22 + I-520 A 520 1.2 + I-519A 520 1.2 + I-998 AG 525 0.88 ++ I-997 AG 525 0.88 ++ I-1544 N 494 1.4++ I-1543 N 523 0.68 +++ I-654 A 556 1.41 + I-653 A 556 1.41 +++ I-652 A556 1.41 +++ I-518 A 516 1.16 ++++ I-517 A 516 1.16 ++ I-1061 A 512 1.22++ I-1060 A 512 1.23 ++++ I-704 A 514 1.3 ++ I-952 A, Example 2, T 4931.04 +++ I-1525 N 535 0.7 ++ I-707 A, Example 491 1.23 +++ 2, A, R, AKI-705 A 526 1.11 ++ I-996 AF 510 0.92 ++ I-995 AF 510 0.92 ++ I-1141 Z558 1.2 ++ I-507 AD 466 0.79 ++ I-506 AD 466 0.76 ++ I-505 Q 516 0.94 ++I-504 Q 502 0.83 ++ I-1535 A 515 1.08 +++ I-606 A 546 0.86 ++ I-538 AA,T 541 1.28 ++ I-1528 A 558 1.26 ++ I-1527 A 496 1.16 ++ I-1569 A 510 1.2++ I-1130 A 495 1.26 +++ I-1524 A 469 1.19 ++ I-1523 A 496 1.5 ++ I-1521A 506 1.36 ++ I-1519 A 557 1.42 ++ I-1063 AA, W, T 538 1.17 +++ I-1542 A475 1.17 +++ I-1514 A 449 1.11 +++ I-1510 A 537 1.34 +++ I-1145 A,Example 2 543 0.94 ++ I-1104 A 508 1.37 ++ I-1103 A 508 1.37 ++++ I-992H, R, Example 2 522 0.73 ++ I-1102 A 508 1.36 ++++ I-1138 N 496 1.08 ++I-974 N 500 0.94 ++ I-851 K, Example 2, A 526 1.04 +++ I-635 N, R 4811.07 ++ I-539 AA, W, T 542 1.11 ++ I-658 A, Example 2, A 551 1.33 ++I-650 A 538 1.4 ++ I-649 A 538 1.4 +++ I-1144 A 544 1.3 ++ I-576 A, B523 1.04 ++ I-1461 N 516 1.23 ++ I-648 A 538 1.4 ++ I-515 A 480 1.07 ++I-514 A 480 1.07 +++ I-513 A 480 1.07 +++ I-967 AD, N, Example 2 4810.63 ++ I-655 K, Example 2, AD 477 1.29 ++ I-803 A, Example 2, T 4790.97 +++ I-574 A, Example 2, B 481 0.95 +++ I-824 A, N, Example 2a 5500.84 +++ I-639 N 551 1.24 ++ I-1501 AD 480 1.3 ++ I-1499 AD 506 0.9 ++I-1496 A 548 0.63 ++ I-1493 A 520 1.02 ++ I-1492 A 531 1.19 ++ I-1490 A513 1.15 ++ I-1487 A 508 0.64 +++ I-1058 A 510 1.39 +++ I-572 A, Example2, B 481 0.96 + I-589 AH, W, A, Example 507 1.07 ++ 2, T I-703 A 4520.89 ++ I-641 Example 83, A 544 1.12 ++ I-1708 AD 464 0.85 ++ I-1468I-1468 548 0.65 ++ I-993 H, R, Example 2 531 0.84 ++ I-640 Example 83, A496 1.03 ++ I-664 D, Example 2 532 1.12 ++ I-663 D, Example 2 532 1.12 +I-492 AD 480 0.81 ++ I-1448 AD 529 0.74 ++ I-1433 C 581 1.16 ++ I-1432 C513 0.94 ++ I-1431 C 487 0.84 ++ I-1428 C 583 1.23 ++ I-1425 C 563 1.17++ I-1422 C 583 1.24 ++ I-1421 C 568 1.09 ++ I-1417 C 487 0.87 ++ I-1406C 583 1.25 ++ I-1400 C 554 0.76 ++ I-1395 A 521 0.85 ++ I-1383 A 5141.08 ++ I-1380 A 531 1.12 ++ I-1377 A 477 0.93 ++ I-965 A, R 409 0.73 ++I-964 A, R 409 0.79 ++ I-989 A 526 1.07 ++ I-665 Example 38, A 536 1.29++ I-662 D, Example 2 532 1.11 + I-1325 O 562 1.35 ++ I-1324 O 562 1.3++ I-1363 O 522 1.16 ++ I-1320 O 503 1.16 ++ I-1318 O 579 1.42 ++ I-1314O 575 0.9 +++ I-1313 O 575 0.87 +++ I-1307 O 521 0.91 ++ I-1295 O 4811.44 ++ I-475 H 509 1.43 ++ I-1289 O 467 1.3 ++ I-823 N 548 0.85 +++I-632 S 482 1.06 ++ I-1285 O 554 1.57 ++ I-1800 H 524 1.2198 ++++ I-1801A, S, AL 514 1.3533 ++++ I-814 F 563 1.27 +++ I-627 A 496 1.26 ++ I-1257N 542 1.16 +++ I-1277 N 511 1.09 ++ I-1191 N 516 1.09 ++ I-1234 N 5701.09 ++ I-950 T, Example 2, T 493 1 ++ I-621 A 478 1.25 ++ I-510 A 5310.9 + I-706 AD 490 1.33 ++ I-1232 N 486 0.71 ++ I-500 X 489 1.39 + I-511A, Example 2 517 0.9 + I-531 A 453 1.05 ++ I-624 A 492 1.29 +++ I-625 A504 1.27 ++ I-499 N, Example 2a 478 0.64 +++ I-498 N, Example 2a 4780.68 ++++ I-1216 N 533 1.2 ++ I-1082 N 525 1.59 ++ I-1211 N 520 0.85 ++I-1209 N 520 0.72 +++ I-1208 N 534 0.81 ++ I-1205 N 553 1.62 ++ I-1202 N477 1.2 ++ I-1200 N 463 1.32 +++ I-1199 N 463 1.29 ++ I-1197 N 520 0.74+++ I-1196 N 495 1.19 ++ I-1194 N 522 0.68 ++ I-1158 N 500 0.77 ++I-1155 N 499 1.31 +++ I-1402 N 507 1.01 ++ I-1151 N 520 0.71 +++ I-1149N 495 1.15 ++ I-1146 N 520 0.69 +++ I-1187 N 513 1.37 ++ I-615 A 4921.32 +++ I-614 AD 429 1.14 + I-620 A 478 1.21 +++ I-469 A 448 1.25 ++I-467 A 486 1.25 ++ I-464 A 440 1.24 +++ I-452 E 493 0.76 ++ I-449 E 4950.68 ++ I-446 E 516 0.69 ++ I-443 E 547 0.68 ++ I-440 E 556 0.73 ++I-437 E 539 0.83 ++ I-434 E 495 0.66 ++ I-431 E 491 0.69 ++ I-425 AD 4591.3 ++ I-11 K 488 0.99 + I-423 A 506 1.41 ++ I-422 A 517 1.31 + I-419 A534 1.09 ++ I-416 E 533 0.85 ++ I-51 G 476 0.76 ++ I-409 H 557 0.97 ++I-406 H 509 1.32 ++ I-403 H 518 1.2 ++ I-401 H 557 1.19 ++ I-399 H 5391.73 ++ I-393 H 509 1.29 + I-390 H 518 1.19 ++ I-387 H 489 1.14 ++ I-385H 486 1.17 ++ I-844 H, N 568 0.72 ++++ I-369 H 557 0.85 ++ I-1214 H 4710.89 ++ I-362 H 513 1.46 + I-359 H 495 1.32 ++ I-350 H 541 1.11 ++ I-347H 504 1.59 ++ I-333 H 567 1.18 ++ I-330 H 488 1.48 ++ I-50 AD 511 0.85 +I-44 E 480 1.34 ++ I-317 A 516 1.78 +++ I-315 A 482 1.75 ++ I-314 A 4791.15 +++ I-312 A 453 1.75 ++ I-309 A 484 1.94 ++ I-306 A 514 1.33 ++I-304 A 488 1.6 ++ I-303 A 482 1.55 ++ I-302 A 482 1.54 +++ I-296 A 4861.61 ++ I-294 A 494 1.42 ++ I-49 A 461 1.3 +++ I-291 A 542 1.3 ++ I-290K, Example 2, A 488 1.44 ++ I-289 K, Example 2, A 420 1.24 +++ I-287 A465 1.15 ++ I-284 AD 401 0.96 ++ I-283 A 504 1.41 ++ I-282 A 515 1.29 ++I-281 A 460 0.98 ++ I-280 K, Example 2, A 464 1.41 ++ I-279 AD 415 1.06++ I-278 P 430 1.34 + I-277 A 462 1.24 ++ I-48 A 447 1.2 ++ I-276 A 4701.45 ++ I-274 A 496 1.29 ++ I-272 A 474 1.01 ++ I-271 A 408 1.08 ++I-268 A 466 1.25 ++ I-31 A 472 0.9 ++ I-26 A 436 1.19 + I-267 A 478 1.24+++ I-266 A 448 1.23 ++ I-35 A 428 1.25 ++ I-28 A 462 1.35 ++ I-1139 A486 1.46 ++++ I-34 A 462 1.33 + I-264 A 462 1.17 + I-27 A 436 1.3 ++I-259 A, Example 2, A 475 0.95 ++ I-33 A 462 1.43 ++ I-30 A 395 0.76 ++I-29 A 400 1.11 + I-38 A 412 1.02 ++ I-25 A 450 1.49 +++ I-252 A 4971.29 +++ I-23 X 485 1.3 +++ I-233 K, Example 2, A 479 1.27 +++ I-232 A479 1.29 +++ I-230 K, Example 2, A 465 1.05 ++ I-229 K, Example 2, A 4481.04 ++ I-227 K, Example 2, A 446 1 + I-226 K, Example 2, A 494 1.34 ++I-224 A 498 1.66 +++ I-223 K, Example 2, A 498 1.39 +++ I-221 K, Example2, A 490 1.21 ++ I-218 K, Example 2, A 494 1.32 ++ I-214 K, Example 2, A494 1.3 +++ I-213 K, Example 2, A 498 1.52 ++ I-212 K, Example 2, A 4781.43 +++ I-211 K, Example 2, A 478 1.42 +++ I-210 K, Example 2, A 4821.36 ++ I-209 K, Example 2, A 466 1.26 ++ I-206 K, Example 2, A 462 1.31++ I-203 K, Example 2, A 490 1.26 + I-200 K, Example 2, A 458 1.37 ++I-197 K, Example 2, A 458 1.39 ++ I-195 K, Example 2, A 422 1.24 +++I-194 K, Example 2, A 408 1.15 ++ I-191 K, Example 2, A 431 0.92 ++I-190 A 448 1.23 +++ I-189 K, Example 2, A 436 1.32 +++ I-20 A, Example2a 459 0.81 ++ I-184 A 487 0.95 +++ I-182 A 523 1.07 ++ I-19 A, S 4461.02 ++ I-181 A 487 1.01 ++ I-179 A 473 0.92 +++ I-178 A 461 1.23 ++I-177 A 461 1.29 ++++ I-176 A 462 1.04 ++ I-175 A 462 1.04 ++++ I-173 A535 1.11 +++ I-172 A 473 0.93 ++ I-18 S 446 0.98 + I-170 F 515 0.93 +I-164 A, C 523 1.03 +++ I-160 A 447 0.84 +++ I-158 A 394 1.04 ++ I-157 A460 1.21 +++ I-156 A 470 1.38 +++ I-155 A 434 0.83 ++ I-154 A 368 0.9 ++I-153 A 430 1.2 ++ I-152 A 486 1.26 ++ I-150 A 509 1.44 ++++ I-147 A 4461.0237 ++ I-145 A 540 1.5492 ++++ I-144 A 540 1.54 ++ I-861 A 4641.1238 + I-143 A 464 1.1238 ++ I-142 A 526 1.4591 ++++ I-141 A 5261.4591 ++ I-45 C 549 1.04 +++ I-121 L 501 0.7002 + I-119 L 487 0.7118+++ I-13 L 459 1.08 ++ I-115 A 499 1.2061 ++ I-111 A 523 0.9237 ++ I-108A 501 0.9267 ++ I-106 A 523 0.9933 ++ I-105 A 399 0.8414 +++ I-102 A 4820.7118 + I-4 D 473 1.29 + I-83 A 483 1.1 ++ I-78 A 428 1.058 +++ I-73 A522 1.4567 +++ I-72 A 472 1.35 ++++ I-70 K, Example 2, A 473 1.08 +++I-69 A 536 1.59 +++ I-68 A 486 1.46 ++++ I-67 K, Example 2, A 540 1.62++++ I-66 A 540 1.54 +++ I-65 K, Example 2, A 490 1.43 ++++ I-62 K,Example 2, A 488 1.35 + I-61 K, Example 2, A 438 1.19 +++ I-60 K,Example 2, A 502 1.51 + I-59 K, Example 2, A 452 1.35 +++ I-57 A 410 1+++ I-55 A 589 1.14 ++ I-1 A 410 1.03 +++ ++++ indicates an IC₅₀ of lessthan about 0.2 μM, +++ indicates an IC₅₀ between about 0.2 μM and about1 μM, ++ indicates an IC₅₀ between about 1 μM and about 10 μM, and +indicates an IC₅₀ greater than 10 μM.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein, Such equivalents areintended to be encompassed in the scope of the following claims.

1-13. (canceled)
 14. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is C, S, orS(O); X₂ is CR₇ or N; R₁ is H, D, —OH, —SH, —NH₂, —NH(C₁-C₄) alkyl,—N((C₁-C₄) alkyl)₂, or F; R₂ is (C₁-C₈) alkyl, aryl, heteroaryl, (C₃-C₈)cycloalkyl, heterocyclyl, —NR₁₀R₁₁, or —OR₁₀, wherein alkyl, aryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moreR₈; each R₃ is independently at each occurrence selected from D, (C₁-C₆)alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, aryl, heteroaryl, (C₃-C₈) cycloalkyl,heterocyclyl, —CN, —OH, —C(O)R₁₇, —C(O)OR₁₇, —OC(O)OR₁₇, —OC(O)NR₁₇R₁₈,—NR₁₇R₁₈, —NR₁₇C(O)R₁₈, —NR₁₇C(O)OR₁₈, —C(O)NR₁₇R₁₈, —NR₁₇C(O)NR₁₇R₁₈,—S(O)_(q)NR₁₇R₁₈, —S(O)_(q)R₁₇R₁₈, —NR₁₇S(O)_(q)R₁₇R₁₈, or halogen,wherein alkyl is optionally substituted with one or more substituentsindependently selected from —OH or —NH₂; or two R₃ together when onadjacent carbons form a (C₃-C₅) cycloalkyl optionally substituted withone or more R₁₉; or two R₃ together form a (C₃-C₈) spirocycloalkyloptionally substituted with one or more R₁₉; or two R₃ together form aspiroheterocyclyl optionally substituted with one or more R₁₉; or two R₃together when on adjacent carbons form an aryl ring optionallysubstituted with one or more R₁₉; or two R₃ together when on adjacentcarbons form an heteroaryl ring optionally substituted with one or moreR₁₉; R₄ is (C₁-C₆) alkyl, —(C₀-C₃) alkylene-aryl, heteroaryl, (C₃-C₈)cycloalkyl, CD₃, or heterocyclyl, wherein aryl, heteroaryl, heterocyclyland cycloalkyl are optionally substituted with one or more R₁₂; R₅ andR_(5′) are independently H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆)alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, orhalogen; or R₅ and R_(5′) together form a (C₃-C₆) cycloalkyl orheterocyclyl ring optionally substituted with one or more substituentsindependently selected from halogen, —CN, (C₁-C₆) alkyl, —OH, —CH₂OH,—(C₀-C₂)-alkylene-O(C₁-C₆) alkyl, or —(C₀-C₂)-alkylene-NR₁₇R₁₈; R₆ isindependently H, D, halogen, —CN, —NR₁₇R₁₈, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, or —OH when X₂ is N; R₇ is H, D, (C₁-C₆) alkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,halogen, aryl, heteroaryl, —CN, or —NR₁₀R₁₁, wherein aryl and heteroarylis optionally substituted with one or more R₁₀; each R₈ is independentlyat each occurrence selected from D, (C₁-C₆) alkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, —(C₁-C₃)-alkylene-O(C₁-C₆) alkyl,—(C₀-C₄)-alkylene-aryl, —(C₀-C₄)-alkylene-heteroaryl, (C₃-C₁₀)cycloalkyl, heterocyclyl, —(C₀-C₄)-alkylene-O-aryl,—(C₀-C₄)-alkylene-O-heteroaryl, —O—(C₃-C₅)cycloalkyl, —S-heteroaryl,halogen, —CN, —C(O)R₁₀, —CO(O)R₁₀, —C(O)NR₁₀R₁₁, —S(O)_(q)R₁₀,—S(O)_(q)NR₁₀R₁₁, —NR₁₀S(O)_(q)R₁₁, —(C₀-C₃)-alkylene-NR₁₀R₁₁,—NR₁₀C(O)R₁₁, —NR₁₀C(O)C(O)R₁₁, —NR₁₀C(O)NR₁₀R₁₁, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅, or —OH, wherein alkyl, alkylene, aryl,heteroaryl, and heterocyclyl are optionally substituted with one or moreR₉; or two R₈ together when on adjacent carbons form an aryl ringoptionally substituted with one or more R₉; or two R₈ together when onadjacent carbons form a heteroaryl ring optionally substituted with oneor more R₉; or two R₈ together when on adjacent carbons form aheterocyclyl ring optionally substituted with one or more R₉; each R₉ isindependently at each occurrence selected from D, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₃-C₈) cycloalkyl, halogen, aryl, —OH, —CN, —C(O)R₁₀,—C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀R₁₁, —S(O)_(q)R₁₀, —S(O)_(q)NR₁₀R₁₁,—NR₁₀S(O)_(q)R₁₁, oxo, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂, —SiMe₃, SF₅,—O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, and cycloalkyl areoptionally substituted with one or more substituents independentlyselected from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, halogen,aryl, —NR₁₄C(O)R₁₅, —NR₁₄S(O)_(q)R₁₅, —OH or —CN; or two R₉ togetherwhen on adjacent carbons form an aryl ring; or two R₉ together when onadjacent carbons form a heteroaryl ring; or two R₉ together when onadjacent carbons form a (C₃-C₁₀) cycloalkyl ring; each R₁₀ and R₁₁ isindependently at each occurrence selected from H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —(C₀-C₃) alkylene-aryl, —(C₀-C₄)alkylene-(C₃-C₅) cycloalkyl, —(C₀-C₄) alkylene-heterocyclyl, —(C₀-C₄)alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene,cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more substituents independently selected from(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,(C₃-C₅) cycloalkyl, heterocyclyl, aryl, —S(O)_(q)(C₁-C₃) alkyl,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)R₁₅, halogen, —OH, or —CN; or R₁₀and R₁₁ together form a heterocyclyl ring optionally substituted withone or more substituents selected from oxo, —C(O)(C₁-C₃) alkyl or—NR₁₄NR₁₅; each R₁₂ is independently at each occurrence selected from D,(C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₃-C₅) cycloalkyl,aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocyclyl,—O—(C₃-C₅)cycloalkyl, —S(O)_(q)R₁₀, —(CH₂)_(p)C(O)OR₁₀, —C(O)NR₁₄R₁₀,—S(O)_(q)NR₁₄R₁₅, —NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₀,—NR₁₄SO_(q)R₁₀, —NR₁₄COR₁₀, halogen, —P(O)((C₁-C₆)alkyl)₂, —P(O)(aryl)₂,—SiMe₃, SF₅ or —OH, wherein alkyl, aryl, heteroaryl, heterocyclyl, andcycloalkyl are optionally substituted with one or more R₁₃; each R₁₃ isindependently at each occurrence selected from D, (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₁-C₆) alkoxy, halogen, (C₁-C₆) haloalkoxy, (C₁-C₆)hydroxyalkyl, heterocyclyl, heteroaryl, aryl, —OR₁₄, —C(O)R₁₄,—C(O)NR₁₄R₁₅, —NR₁₄R₁₅, —S(O)_(q)R₁₄, —NR₁₄S(O)_(q)R₁₅,—S(O)_(q)NR₁₄R₁₅, —NR₁₄C(O)NR₁₄R₁₅, —NR₁₄C(O)OR₁₅, —P(O)((C₁-C₆)alkyl)₂,—P(O)(aryl)₂, —SiMe₃, SF₅ or —CN, wherein alkyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl are substituted with one or moresubstituents independently selected from (C₁-C₆) alkyl, —NR₁₄C(O)R₁₅,—OH, —CN, —C(O)R₁₄, or —NR₁₄R₁₅; or two R₁₃ together when on adjacentcarbons form a heterocyclyl ring optionally substituted with one or moreR₁₆; or two R₁₃ together when on adjacent carbons form a heteroaryl ringoptionally substituted with one or more R₁₆; or two R₁₃ together withthe carbon to which they are attached can form a spiroheterocyclyloptionally substituted with one or more R₁₆; each R₁₄ and R₁₅ areindependently at each occurrence selected from H, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —(C₁-C₄) alkylene-(C₃-C₈) cycloalkyl, —(C₀-C₄)alkylene-heterocyclyl, —(C₀-C₄) alkylene-aryl, —(C₀-C₄)alkylene-heteroaryl, or —CN, wherein alkyl, alkenyl, alkynyl, alkylene,cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more R₁₆; or R₁₄ and R₁₅ together form aheterocyclyl ring optionally substituted with one or more R₁₆; each R₁₆is independently at each occurrence selected from D, (C₁-C₆) alkyl,(C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) haloalkyl, (C₁-C₆) alkoxy,(C₁-C₆) haloalkoxy, —C(O)(C₁-C₃) alkyl, —NHC(O)(C₁-C₄) alkyl, —CN,—CH₂CN, —CR₁₀R₁₁NR₁₀R₁₁, oxo, —NR₁₀R₁₁, —S(O)_(q)(C₁-C₆) alkyl,—C(O)NR₁₀R₁₁, —S(O)_(q)NR₁₀R₁₁, —NR₁₀C(O)R₁₀R₁₁, —NR₁₀C(O)NR₁₀R₁₁, or—OH; or two R₁₆ together when on adjacent carbons form an aryl ring; ortwo R₁₆ together when on adjacent carbons form a spiroheterocyclyl ring;each R₁₇ and R₁₈ is at each occurrence independently H or (C₁-C₆) alkyl;R₁₉ is independently at each occurrence H, D, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, halogen, —CN, or —NR₁₇R₁₈; m is 0, 1 or 2; n is 0, 1, 2 or3; p is 0, 1, or 2; and each q is 0, 1, or
 2. 15. The compound of claim14, having Formula (Ia):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim14, having Formula (Ib):

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim14, having Formula (Ic): or a pharmaceutically acceptable salt thereof.18. The compound of claim 14, having Formula (Id):

or a pharmaceutically acceptable salt thereof.


19. The compound of claim 14, having Formula (Ie):

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim14, having Formula (If):

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim14, having Formula (Ig):

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim14, having Formula (Ih):

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim14, having Formula (Ii):

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim14, having Formula (Ij):

or a pharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising, a compound of claim 14 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 26.A method of treating a disease or disorder associated with modulation ofUSP7 comprising, administering to a patient in need thereof an effectiveamount of a compound of claim
 14. 27. A method of inhibiting USP7comprising administering to a patient in need thereof an effectiveamount of a compound of claim
 14. 28. A method of treating cancer, themethod comprising administering to a patient in need thereof aneffective amount of a compound of claim
 14. 29. A method of treating aneurodegenerative disease, the method comprising administering to apatient in need thereof an effective amount of a compound of claim 14.30. A method of treating a viral infection and disease, the methodcomprising administering to a patient in need thereof an effectiveamount of a compound of claim
 14. 31. A method of treating aninflammatory disease or condition, the method comprising administeringto a patient in need thereof an effective amount of a compound of claim14.
 32. A method of inducing cell cycle arrest, apoptosis in tumorcells, and/or enhanced tumor specific T-cell immunity, the methodcomprising contacting the cells with an effective amount of a compoundof claim 14.